Apparatus for extracorporeal blood treatment

ABSTRACT

An extracorporeal blood treatment apparatus includes a filtration unit (2) connected to a blood circuit (17) and a dialysate circuit (32), a preparation device (9) for preparing and regulating the composition of the dialysis fluid, and a sensor (11) for measuring conductivity of the dialysate (i.e. spent dialysis fluid); a control unit (12) configured for setting a sodium concentration in the dialysis fluid and after setting the dialysis fluid at the initial set point, circulating the dialysis fluid and blood through the filtration unit (2), measuring an initial conductivity value of the dialysate at the beginning of the treatment, and calculating, based on the measured initial conductivity value and on the corresponding conductivity value of the dialysis fluid, the value of the initial plasma conductivity, said circulating of the dialysis fluid up to the calculating of the initial plasma conductivity performed by maintaining the dialysis fluid conductivity substantially constant.

PRIORITY CLAIM

The present application is a continuation of U.S. application Ser. No.15/574,956, filed Nov. 17, 2017, which is a National Phase ofInternational Application No. PCT/EP2016/061568, filed May 23, 2016,which claims priority to Swedish Patent Application No. 1550667-8, filedMay 25, 2015. The entire contents of each application listed above isherein incorporated by reference and relied upon.

TECHNICAL FIELD

The present invention relates to an apparatus for extracorporeal bloodtreatment and a method for controlling the extracorporeal bloodtreatment apparatus.

In particular, the invention may be used for regulating the conductivityof a dialysis liquid during a hemodialysis or hemodiafiltrationtreatment.

In more detail, the apparatus and the method are particularly adaptedfor properly regulating the concentration of sodium in the dialysisliquid, particularly to run an isotonic or an isonatremic or anisonatrikalemic dialysis treatment.

BACKGROUND OF THE INVENTION

The kidneys fulfil many functions, including the removal of water, theexcretion of catabolites (or waste from the metabolism, for example ureaand creatinine), the regulation of the concentration of the electrolytesin the blood (e.g. sodium, potassium, magnesium, calcium, bicarbonates,phosphates, chlorides) and the regulation of the acid/base equilibriumwithin the body, which is obtained in particular by the removal of weakacids and by the production of ammonium salts.

In individuals who have lost the use of their kidneys, since theseexcretion and regulation mechanisms no longer work, the body accumulateswater and waste from the metabolism and exhibits an excess ofelectrolytes, as well as, in general, acidosis, the pH of the bloodplasma shifting downwards, below 7.35 (the blood pH normally varieswithin narrow limits of between 7.35 and 7.45).

In order to overcome renal dysfunction, resort is conventionally made toa blood treatment involving extracorporeal circulation through anexchanger having a semipermeable membrane (dialyzer) in which thepatient's blood is circulated on one side of the membrane and a dialysisliquid, comprising the main electrolytes of the blood in concentrationsclose to those in the blood of a healthy subject, is circulated on theother side.

Furthermore, a pressure difference is created between the twocompartments of the dialyzer which are delimited by the semipermeablemembrane, so that a fraction of the plasma fluid passes byultrafiltration through the membrane into the compartment containing thedialysis liquid.

The blood treatment which takes place in a dialyzer as regards wastefrom the metabolism and electrolytes results from two mechanisms ofmolecular transport through the membrane.

On the one hand, the molecules migrate from the liquid where theirconcentration is higher to the liquid where their concentration islower. This is diffusive transport.

On the other hand, certain catabolites and certain electrolytes areentrained by the plasma fluid which filters through the membrane underthe effect of the pressure difference created between the twocompartments of the exchanger. This is convective transport.

Three of the abovementioned functions of the kidney, namely the removalof water, the excretion of catabolites and the regulation of theelectrolytic concentration of the blood, are therefore performed in aconventional blood treatment device by the combination of dialysis andblood filtration (this combination is referred to as hemodialysis).

As regards the regulation of the acid/base equilibrium inside the body,the approach adopted to overcome renal deficiency is to act on amechanism by which the acid/base equilibrium inside the body isregulated, this mechanism consisting of the buffer systems of the blood,the main one of which comprises carbonic acid, as a weak acid,associated with its alkali salt, bicarbonate. This is why, in order tocorrect acidosis in a patient suffering from renal insufficiency, he isadministered with bicarbonate via the vascular route, directly orindirectly, during a hemodialysis session.

Moreover, it must be underlined that sodium is the main ionic solute ofextracellular volume. From literature search and according to the mainopinion leaders in the dialysis field, the determination of dialysisfluid sodium concentration to be used during the dialysis treatmentappears as one of the major challenges of dialysis prescription.

The dialysis fluid sodium concentration significantly affects the sodiumbalance and the intracellular hydration of the patient with implicationson hemodialysis tolerance and also long term patient survival.

Hypertonic dialysis fluid sodium prescription will result in a positivesodium balance followed by a water shift from the intracellular toextracellular compartment. The intracellular dehydration increasesvasopressin release and provokes thirst with the consequence of agreater inter-dialytic weight gain and hypertension.

On the contrary, a dialysis fluid sodium concentration that is too low(i.e., hypotonic) will provoke a negative sodium gradient with a watershift in the intracellular compartment, which is responsible forintra-dialytic cramps, headache, hypovolemia and risk of hypotension.

One of current opinions is the idea that sodium balance should bemaintained null during a dialysis treatment: this is based on theso-called “sodium set point” theory, according to which both healthysubjects and dialysis patients tend to maintain a stable extra-cellularsodium concentration.

As above mentioned, sodium is removed during dialysis through convectionand diffusion. The main sodium removal process during dialysis isconvective. If we assume that the ultrafiltrate fluid is basicallyisotonic, convection does not change the tonicity of the extracellularfluid.

There is a need to help the physician to prescribe a “physiological”dialysis fluid composition to treat the patient.

Moreover, a second need is to have a bio-sensing-based therapy which iseasy to use and designed also for operators not very skilled or workingin crowded and very busy dialysis rooms.

To at least partly solve the above mentioned drawbacks, document U.S.Pat. No. 4,508,622 teaches a dialysis device in which the electrolytecomposition of the untreated and treated fluids routed through thedialyzer may be determined and the composition of the dialysis solutionadapted to the patient's requirements.

A first electrolyte detector (conductivity cell) is provided upstream ofthe dialyzer and a second electrolyte detector (conductivity cell) isprovided downstream of the dialyzer. Each detector is coupled to areadout element through which both of the values of the dialysissolution may be observed and eventually controlled. In more detail, theapparatus according to U.S. Pat. No. 4,508,622 consists essentially of aunit for production of the dialysis solution and a dialyzer connected tothe unit and followed downstream by a pump to produce a vacuum in thedialyzer on the side of the dialysis fluid. The detector mountedupstream of the dialyzer, and connected with a control unit, measuresthe conductivity of the total dialysis solution.

A second detector is mounted downstream of dialyzer and is connectedwith a comparator which is, in turn, connected to a differentiationunit. A control signal is provided by the differentiation unit tocontrol unit if there is a difference in the differentiation unit thatdeviates from the predetermined nominal value.

During dialysis fluid circulation, if detector generates a signal to theevaluation unit and subsequently to the differentiation unit whichdeviates by a certain amount from the signal generated by detector,i.e., a difference in value appears which deviates from thepredetermined value for differentiation unit, the difference unitactivates the control unit, which in turn switches concentrate pump onor off as a function of the higher or lower concentration in thedialysis solution to be produced. A treatment in which the dialysisfluid has the same conductivity of the blood and of the spent dialysisfluid, is one of the described implementations.

However, the dialysis fluid and the blood reach the same conductivityafter a certain time lapse which clearly affects the pre-dialytic plasmasodium content. Therefore, the method described in U.S. Pat. No.4,508,622 in not properly an ‘isoconductive’ dialysis treatment.

In any case, ‘isoconductive’ dialysis has been shown to lead toundesired sodium loading in the patient.

Moreover, the prior art devices include dialysis apparatus wherein theconductivity of dialysis fluid is controlled in order to reach a desiredpost-dialysis plasmatic conductivity, i.e. conductivity (or sodiumconcentration) of the patient's blood at the end of the dialysistreatment.

It is known, for example from EP 1389475, a dialysis apparatus providedwith a conductivity system that computes the dialysis fluid conductivity(corresponding to the dialysis fluid sodium concentration) from periodicmeasurements of the sodium blood concentration allowing the sodium levelof the patient to reach a prescribed end-of-session value.

This dialysis apparatus includes a bag and a pump for infusing a patientwith an infusion solution containing sodium at a determined and knownconcentration.

A structure for determining the sodium concentration [Na⁺]_(dial) of thedialysis liquid is also provided so that the patient's body tendstowards a desired sodium concentration [Na⁺]_(des), as a function of thedialysance D for sodium of the dialyser, of the desired sodiumconcentration [Na⁺]_(des) inside the patient's body, of the infusionflow rate and of the sodium concentration [Na⁺]_(sol) of the infusionsolution.

A control unit drives the pump for regulating the sodium concentrationof the dialysis liquid such that this concentration is equal (tendstowards) to the determined concentration [Na⁺]_(dial).

As previously mentioned, one of the problems of the dialysis apparatusof the discussed prior art is presently the choice of the appropriatepost-dialysis plasmatic conductivity target.

EP 2377563 discloses a dialysis apparatus comprising a blood treatmentunit with an online preparation device for preparing a dialysis fluidcontaining sodium and comprising a dialysis preparation section forregulating the concentration of sodium in the dialysis fluid. The bloodcircuit is configured to circulate extracorporeal blood through theblood chamber; control means determines a value representative of thesodium concentration in the blood and are programmed for driving thedialysis preparation section as a function of the determined plasmasodium value, such that the substance concentration in the dialysisfluid tends towards the substance concentration in the blood.

The plasma sodium content is determined by measuring the inlet andoutlet conductivities of the dialysis fluid upstream and downstream thedialyzer, by then changing the conductivity upstream the filter by aprefixed step and measuring a second time the inlet and outletconductivities of the dialysis fluid upstream and downstream thedialyzer with the modified conductivity value.

With the methods described, for example in EP 547025 or in EP 920877, itis possible to determine the plasma conductivity and thereby to properlyregulate the dialysis fluid preparation section.

The described system however changes the blood conductivity and tonicitysince the dialysis fluid enters into contact and exchange significantlywith blood before a plasma conductivity calculation; the effect onplasma conductivity is in an amount proportional to the differencebetween blood and dialysis fluid conductivities.

Finally, document U.S. Pat. No. 8,182,692 describes a dialysis apparatusproviding a treatment in which a dialysis fluid having a sodiumconcentration substantially equal to the estimated current sodiumconcentration in the patient's blood is performed by placing thedialysis fluid in communication with the patient's blood across thesemi-permeable membrane to perform a dialysis treatment on the patient'sblood without substantially altering the sodium concentration of thepatient's blood during the performance of the dialysis treatment.

In more detail, a solution supply device, containing aconductivity-testing solution, is selectively placed in communicationwith dialyzer and the blood flowing therein.

According to this patent, any subject, including hemodialysis patients,has a set level of sodium in his body, referred to as the “set point.”The set point of a subject tends to remain relatively constant, andsodium levels deviating too far from the set point may cause discomfortto the subject. Given the above, the method of the prior art includescausing blood to flow through blood conduit of the dialyzer and flowingthe conductivity-testing solution in the opposite direction through thedialyzer.

Conductivity detectors measure the conductivity of conductivity-testingsolution as the solution enters and exits dialyzer. Conductivity-testingsolution is formulated such that electrically conductive solutes otherthan sodium in the patient's blood have little or no effect on theconductivity measurements of conductivity-testing solution.

According to U.S. Pat. No. 8,182,692, due to the closely matchedconcentrations of electrically conductive solutes, such as phosphate,sulfate, bicarbonate, potassium, calcium, and magnesium, inconductivity-testing solution and in the patient's blood, littlediffusion of those electrically conductive solutes occurs acrossmembrane. Consequently, the conductivity measurements ofconductivity-testing solution is closely correlated with the level ofsodium in the patient's blood.

Therefore, conductivity-testing solution is exclusively used toaccurately determine the level of sodium in the patient's blood as afunction of the change in conductivity across dialyzer of theconductivity-testing solution.

Control unit then determines the level of sodium in the patient's bloodas a function of the measured conductivity values.

After determining the concentration of sodium in the patient's blood,dialysis fluid may be prepared to include a concentration of sodium thatis substantially equal to the concentration of sodium determined toexist in the patient's blood.

Moreover, US2012/018379 discloses an apparatus and a method for thedetermination and regulation of the concentration of one dissolvedsubstance (e.g. sodium) in a dialysis fluid circuit of a hemodialysismachine.

The user presets the sodium regulation range before the start of thedialysis using an estimated value for the dialysis fluid sodium requiredto achieve the isonatremic state or a lab measurement of the patientsodium or a value determined by the regulation from earlier treatments.In addition, the distribution volume of the patient is input for theapplication of the model for the correction of the diffusive balance.Furthermore, the initial concentrations of bicarbonate and potassium inthe patient are set. They come from an analysis by means of a blood gasanalyzer before the start of the dialysis treatment.

After the start of the treatment, the dialysis fluid flow and theconductivity are determined upstream and downstream of the dialyzer anda calculation of the updated current bicarbonate and potassiumconcentration in the patient takes place with it being assumed that thepotassium clearance corresponds to the sodium clearance and that thebicarbonate clearance corresponds to 70% of the sodium clearance. Thesodium clearance from the blood flow is estimated until the presence ofthe first clearance measurement.

The calculation of the conductivity balance and of the correction termfor the ion exchange and thus for the sodium balance then takes placefrom these data.

The conductivity of fluids measured upstream and downstream, the sodiumbalance and the correction term for the dialysis fluid conductivitydownstream of the dialyzer are then the input values for the sodiumregulation. The desired conductivity thus determined is finallyconverted into a desired value for the dialysate sodium while takingaccount of the composition of the dialysis concentrate and this presetvalue is transmitted to a metering unit for dialysis fluid preparation.

SUMMARY

An aim of the present invention is providing an extracorporeal bloodtreatment apparatus able to automatically perform a proper setting ofthe dialysis fluid content of a substance, particularly an ionicsubstance, present in the blood as well.

In detail it is an aim of the present invention to provide anextracorporeal blood treatment apparatus with a proper tool helping thephysician to prescribe a “physiological” dialysis fluid composition,particularly to run an isotonic, isonatremic or isonatrikalemic dialysistreatment.

A further aim of the invention is to make available an extracorporealblood treatment apparatus provided with a selectable biosensing-basedtherapy which is easy to use and designed for not skilled operators orusers working in crowded and busy dialysis rooms.

It is an aim of the invention to provide an extracorporeal bloodtreatment machine configured to automatically perform a proper automaticsetting of the dialysis fluid conductivity.

A further aim of the invention is to make available a dialysis apparatusable to provide an automated delivery and control of the dialysisprescription, particularly in order to restore at each dialysis sessionthe proper sodium-water equilibrium to the patient.

At least one of the above-indicated aims is attained by an apparatus anda corresponding method as in one or more of the appended claims, takensingly or in any combination.

According to a first independent aspect of the invention anextracorporeal blood treatment device is provided including

-   -   a filtration unit (2) having a primary chamber (3) and a        secondary chamber (4) separated by a semi-permeable membrane        (5);    -   a blood withdrawal line (6) connected to an inlet of the primary        chamber (3),    -   a blood return line (7) connected to an outlet of the primary        chamber (3), said blood lines being configured for connection to        a patient cardiovascular system;    -   a dialysis supply line (8) connected to an inlet of the        secondary chamber (4);    -   a dialysis effluent line (13) connected to an outlet of the        secondary chamber (4);    -   a preparation device (9) for preparing a dialysis fluid        connected to said dialysis supply line (8) and comprising        regulating means (10) for regulating the composition of the        dialysis fluid,    -   a sensor (11) for measuring a parameter value of the dialysate        in the dialysis effluent line (13), said parameter of the        dialysate being at least one chosen in a group consisting of        conductivity of the dialysate, a conductivity-related parameter        of the dialysate, concentration of at least a substance in the        dialysate and a concentration-related parameter of at least a        substance in the dialysate;    -   a control unit (12) connected to the sensor (11) for receiving        said parameter value of the dialysate, said control unit (12)        being also connected to the regulating means (10) and programmed        for calculating a value representative of the plasma        conductivity, wherein said control unit (12) is configured for:        -   setting a parameter value for the dialysis fluid in the            dialysis supply line (8) at an initial set point, said            parameter of the dialysis fluid being at least one chosen in            a group consisting of conductivity of the dialysis fluid, a            conductivity-related parameter of the dialysis fluid,            concentration of at least a substance in the dialysis fluid            and a concentration-related parameter of at least a            substance in the dialysis fluid;        -   after setting the dialysis fluid parameter value at the            initial set point, circulating the dialysis fluid through            the secondary chamber (4) of the filtration unit (2) so as            to exchange with blood;        -   circulating blood through the primary chamber (3) of the            filtration unit (2);        -   measuring at least an initial value of said parameter of the            dialysate downstream of said secondary chamber (4) at the            beginning of the treatment,        -   calculating, based on the measured initial parameter value            of the dialysate and on the corresponding parameter value of            the dialysis fluid in the supply line (8), the value of the            initial plasma conductivity, said circulating the dialysis            fluid through the secondary chamber (4) up to measuring the            initial value of said parameter of the dialysate downstream            of said secondary chamber used for the calculating of the            initial plasma conductivity being performed maintaining the            dialysis fluid parameter value substantially constant.

According to a further independent aspect of the invention a method forsetting the parameters in an apparatus for extracorporeal bloodtreatment is provided, the apparatus comprising:

-   -   a filtration unit (2) having a primary chamber (3) and a        secondary chamber (4) separated by a semi-permeable membrane        (5);    -   a blood withdrawal line (6) connected to an inlet of the primary        chamber (3),    -   a blood return line (7) connected to an outlet of the primary        chamber (3), said blood lines being configured for connection to        a patient cardiovascular system;    -   a dialysis supply line (8) connected to an inlet of the        secondary chamber (4);    -   a dialysis effluent line (13) connected to an outlet of the        secondary chamber (4);    -   a preparation device (9) for preparing a dialysis fluid        connected to said supply line (2) and comprising regulating        means (10) for regulating the composition of the dialysis fluid,    -   a sensor (11) for measuring a parameter value of the dialysate        in the dialysis effluent line (13), said parameter of the        dialysate being at least one chosen in a group consisting of        conductivity of the dialysate, a conductivity-related parameter        of the dialysate, concentration of at least a substance in the        dialysate and a concentration-related parameter of at least a        substance in the dialysate;    -   a control unit (12) connected to the sensor (11) for receiving        said parameter value of the dialysate, said control unit (12)        being also connected to the regulating means (10) and programmed        for calculating a value representative of the plasma        conductivity of the blood in said blood lines (6, 7), the method        comprising the following steps performed by the control unit:        -   setting a parameter value for the dialysis fluid in the            dialysis supply line (8) at an initial set point, said            parameter of the dialysis fluid being at least one chosen in            a group consisting of conductivity of the dialysis fluid, a            conductivity-related parameter of the dialysis fluid,            concentration of at least a substance in the dialysis fluid            and a concentration-related parameter of at least a            substance in the dialysis fluid;        -   after setting the dialysis fluid parameter value at the            initial set point, circulating the dialysis fluid through            the secondary chamber (4) of the filtration unit (2) so as            to exchange with blood;        -   circulating blood trough the primary chamber (3) of the            filtration unit (2);        -   measuring at least an initial value of said parameter of the            dialysate downstream of said secondary chamber (4) at the            beginning of the treatment,    -   calculating, based on the measured initial parameter value of        the dialysate and on the corresponding parameter value of the        dialysis fluid in the dialysis supply line (8), the value of the        initial plasma conductivity, said circulating the dialysis fluid        through the secondary chamber (4) up to measuring the initial        value of said parameter of the dialysate downstream of said        secondary chamber used for the calculating of the initial plasma        conductivity being performed maintaining the dialysis fluid        parameter value substantially constant.

In a second aspect, according to the previous aspects, the regulatingmeans (10) modify the dialysis fluid composition by changingconductivity of the dialysis fluid and/or by changing the concentrationof at least one substance in the dialysis fluid.

In a 3^(rd) aspect, according to the previous aspects, the preparationdevice (9) prepares a dialysis fluid containing at least a substance,said substance being present in the blood too, said regulating means(10) regulating the concentration of at least said substance in thedialysis fluid.

In a 4^(th) aspect according to the previous aspects, said substance isan ionic substance, in particular said substance being sodium.

In a 5^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to set the parameter value for the dialysisfluid at the initial set point so that a dialysis fluid conductivitymatches a first estimate of the plasma conductivity of the blood.

In a 6^(th) aspect according to anyone of the previous aspects, theparameter value is a concentration value of at least a substance of thedialysis fluid, in particular said substance being sodium.

In a 7^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured for calculating the initial set point ofa substance concentration in the dialysis fluid, a regulation of thedialysis fluid conductivity in the supply line (8) deriving from saidcalculated set point of said substance.

In an 8^(th) aspect according to the 7^(th) aspect, the control unit isconfigured to calculate the initial set point of the substanceconcentration to be set in the dialysis fluid as a function of thedifference in concentration of at least a further substance in thedialysis fluid and the same further substance in the plasma, thesubstance, whose concentration is to be set, being different from thefurther substance.

In a 9^(th) aspect according to the 7^(th) or 8^(th) aspects, thecontrol unit is configured to calculate the initial set point of thesubstance in the dialysis fluid as a function of the concentration of atleast a further substance in the dialysis fluid, the substance, whoseconcentration is to be set, being different from the further substance,optionally the further substance being chosen in the group includingbicarbonate, potassium, calcium, magnesium, acetate, lactate, citrate,phosphate and sulphate, in particular as a function of the concentrationof at least two of said substances, optionally as a function of theconcentration of bicarbonate, potassium, acetate, and/or citrate, in thedialysis fluid.

In a 10^(th) aspect according to anyone of the previous aspects from the7^(th) to the 9^(th), the control unit is configured to calculate theinitial set point of the substance in the dialysis fluid as a functionof the difference in concentration of at least a further substance inthe dialysis fluid and in the plasma, the substance, whose concentrationis to be set, being different from the further substance, said furthersubstance being chosen in the group including bicarbonate, potassium,calcium, magnesium, acetate, lactate, phosphate, sulphate, and citrate,in particular as a function of the difference, in particular a weighteddifference, in concentration of at least two of said substances,optionally as a function of the difference, in particular a weighteddifference, in concentration of bicarbonate, potassium, citrate, and/oracetate in the dialysis fluid and plasma.

In an 11^(th) aspect according to anyone of the previous aspects fromthe 7^(th) to the 10^(th), the control unit is configured to calculatethe initial set point of the substance in the dialysis fluid as afunction of the molar conductivities of at least a substance in thedialysis fluid chosen in the group including acids and salts ofbicarbonate (HCO₃ ⁻), chloride (Cl⁻), acetate (CH₃COO⁻), lactate (C₃H₅O₃⁻), citrate, phosphate (PO₄ ³⁻), and sulphate (SO₄ ²⁻), wherein thesalts are formed with sodium, potassium, calcium, or magnesium, inparticular as a function of the molar conductivities of at least two ofsaid substances, in more detail as a function of the molarconductivities of at least three of said substances, optionally as afunction of the molar conductivities of the four of said substances, forexample sodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodiumacetate (NaCH₃COO), and potassium chloride (KCl), or sodium bicarbonate(NaHCO₃), sodium chloride (NaCl), trisodium citrate (Na₃C₆H₅O₇), andpotassium chloride (KCl).

In a 12^(th) aspect according to anyone of the previous aspects from the7^(th) to the 11^(th), the control unit is configured to calculate theinitial set point of the substance in the dialysis fluid as a functionof an estimated plasma concentration of at least a substance chosen inthe group including sodium, bicarbonate, potassium, acetate, andcitrate, in particular as a function of the estimated plasmaconcentration of at least two of said substances, in more detail as afunction of the estimated plasma concentration of at least three of saidsubstances, optionally as a function of the estimated plasmaconcentration of at least four of said substances included in the groupconsisting of sodium, potassium, calcium, magnesium, bicarbonate,acetate, lactate, citrate, phosphate, and sulphate.

In a 13^(th) aspect according to the 12^(th) aspect, the estimatedplasma concentration of at least a substance chosen in the groupincluding sodium, bicarbonate, potassium, acetate, lactate, and citrateis the mean pre-dialysis values of the corresponding substance for largepatient populations, or historical data of the corresponding substancefor the individual patient or theoretical values of the correspondingsubstance or measured values of the corresponding substance.

In a 14^(th) aspect according to anyone of the previous aspects from the7^(th) to the 13^(th), the control unit is configured to calculate theinitial set point of the substance in the dialysis fluid as a functionof at least one flow rate, in particular the dialysate flow rate at theoutlet of the secondary chamber (4).

In a 15^(th) aspect according to anyone of the previous aspects from the7^(th) to the 14^(th), the control unit is configured to calculate theinitial set point of the substance in the dialysis fluid as a functionof at least an efficiency parameter of the filtration unit (2), inparticular a clearance of the filtration unit (2), optionally the ureaclearance and/or the citrate clearance.

In a 16^(th) aspect according to anyone of the previous aspects from the7^(th) to the 15^(th), the control unit is configured to calculate theinitial set point of sodium concentration in the dialysis fluid usingthe following relationship:

$\begin{matrix}{c_{{di},{Na},{start}} = {{\alpha*c_{{pw},{Na}}} + {\frac{1}{M_{\kappa_{NaCl}}}\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)++}\frac{1}{M_{\kappa_{NaCl}}}\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)} + {\frac{M_{\kappa_{KCl}}}{M_{\kappa_{NaCl}}}{\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)++}\frac{1}{M_{\kappa_{NaCl}}}\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}}} & (I)\end{matrix}$

wherein:

M _(κ) _(NaHCO3) Is the molar conductivity of sodium bicarbonate(NaHCO₃) M _(κ) _(NaCl) Is the molar conductivity of sodium chloride(NaCl) M _(κ) _(NaAc) Is the molar conductivity of sodium acetate(NaCH₃COO) M _(κ) _(KCl) Is the molar conductivity of potassium chloride(KCl) □_(rest3) Is the conductivity contribution from lesser solutes 3c_(di,HCO3) Is the dialysis fluid concentration of bicarbonate c_(di,K)Is the dialysis fluid concentration of potassium c_(di,Ac) Is thedialysis fluid concentration of acetate c_(pw,Na) Is the estimated ormeasured pre-dialysis concentration of sodium ions (Na⁺) in plasma waterc_(pw,HCO3) Is the estimated or measured pre-dialysis concentration ofbicarbonate anions (HCO₃ ⁻) in plasma water c_(pw,Ac) Is the estimatedor measured pre-dialysis concentration of acetate anions (CH₃COO⁻) inplasma water c_(pw,K) Is the estimated or measured pre-dialysisconcentration of potassium ions (K⁺) in plasma water Qdo Is thedialysate flow rate at dialyzer outlet Ku Is the dialyzer clearance forurea α Is the Donnan factor

In a 17^(th) aspect according to anyone of the previous aspects from the7^(th) to the 15^(th), the control unit is configured to calculate theinitial set point of sodium concentration in the dialysis fluid usingthe following relationship:

$\begin{matrix}\left. {c_{{di},{Na},{start}} = {{\alpha \cdot {c_{{pw}_{{Na}^{+}}}++}}\frac{1}{M_{\kappa_{NaCl}}}{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right) \cdot {\left( {{\alpha^{- 1} \cdot c_{{pw}_{{HCO}_{3^{-}}}}} - c_{d_{{HCO}_{3^{-}}}}} \right)++}}{M_{\kappa_{KCl}} \cdot {\left( {{\alpha \cdot c_{{pw}_{K^{+}}}} - c_{d_{K^{+}}}} \right)++}}{\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right) \cdot {\left( {{\alpha^{- 1} \cdot c_{{pw}_{{Ac}^{-}}}} - c_{d_{{Ac}^{-}}}} \right)++}}{\frac{K_{b_{Cit}}}{K_{b}} \cdot \left( {M_{\kappa_{{Na}_{3}{Cit}}} - {3M_{\kappa_{NaCl}}}} \right) \cdot {\left( {{\left( {{0.167\alpha^{- 3}} + {0.125\alpha^{- 2}} + {0.706\alpha^{- 1}}} \right) \cdot c_{{pw}_{{Na}_{3}{Cit}}}} - c_{d_{{Na}_{3}{Cit}}}} \right)++}}{\frac{Q_{do}}{K_{b}} \cdot \kappa_{{rest}3}}}} \right) & ({II})\end{matrix}$

wherein:

M _(κ) _(NaHCO3) Is the molar conductivity of sodium bicarbonate(NaHCO₃) M _(κ) _(NaCl) Is the molar conductivity of sodium chloride(NaCl) M _(κ) _(NaAc) Is the molar conductivity of sodium acetate(NaCH₃COO) M _(κ) _(KCl) Is the molar conductivity of potassium chloride(KCl) M _(Na) ₃ _(Cit) Is the molar conductivity of trisodium citrate(Na₃C₆H₅O₇) □_(rest3) Is the conductivity contribution from lessersolutes 3 c_(di,HCO3) Is the dialysis fluid concentration of bicarbonatec_(di,K) Is the dialysis fluid concentration of potassium c_(di,Ac) Isthe dialysis fluid concentration of acetate c_(di,Na) ₃ _(Cit) Is thedialysis fluid concentration of total citrate c_(pw,Na) Is the estimatedor measured pre-dialysis concentration of sodium ions (Na⁺) in plasmawater c_(pw,HCO3) Is the estimated or measured pre-dialysisconcentration of bicarbonate anions (HCO₃ ⁻) in plasma water c_(pw,Ac)Is the estimated or measured pre-dialysis concentration of acetateanions (CH₃COO⁻) in plasma water c_(pw,K) Is the estimated or measuredpre-dialysis concentration of potassium ions (K⁺) in plasma waterc_(pw,Na) ₃ _(Cit) Is the estimated or measured pre-dialysisconcentration of total citrate in plasma water Qdo Is the dialysate flowrate at dialyzer outlet Ku Is the dialyzer clearance for urea K_(b)_(Cit) Is the dialyzer clearance for citrate α Is the Donnan factor

In a 18^(th) aspect according to anyone of the previous aspects, thesensor (11) is configured to measure a conductivity of the dialysate.

In an 19^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to estimate at least the initial value of theparameter value of the dialysate representative of the conditionsprevailing after the exchange process has reached stable conditions,said estimate being based on at least one measurement of the parametervalue in the dialysate.

In a 20^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to measure at least the initial value ofthe parameter value of the dialysate in the dialysis effluent line (13)downstream of the secondary chamber (4) as soon as the exchange processin the filtration unit (2) reaches stable conditions.

In a 21^(st) aspect according to the previous aspect, the control unit(12) is configured to determine reaching of stable conditions for theexchange process in case one or more of the following conditions occurs:

-   -   a first derivative of the median or of the average value of the        conductivity of the dialysate is lower in size than a first        threshold for a specified time window;    -   a first derivative of the value of conductivity of the dialysate        is lower in size than a first threshold for a specified time        window;    -   a first derivative of the filtered value of conductivity of the        dialysate is lower in size than a first threshold for a        specified time window, the filtered value being a value filtered        either by a median filter or a linear filter, either a finite        impulse response filter, or an infinite impulse response filter;    -   a second derivative of the median value of the conductivity of        the dialysate is lower in size than a second threshold for a        specified time window;    -   a second derivative of the value of conductivity of the        dialysate is lower in size than a first threshold for a        specified time window;    -   a second derivative of the filtered value of conductivity of the        dialysate is lower in size than a first threshold for a        specified time window;    -   a change or a relative change of the value of conductivity of        the dialysate or a filtered version of the value of the        conductivity since a fixed previous point in time is below a        first threshold;    -   a change or the relative change of the value of conductivity of        the dialysate or a filtered version of the value of the        conductivity since a fixed time interval backwards is below a        first threshold;    -   a prefixed time has lapsed after starting circulation of both        blood and dialysis fluid in the filtration unit, in particular        said pre-fixed time being not more than 15 minutes;    -   a variable time has lapsed after starting circulation of both        blood and dialysis fluid in the filtration unit, said variable        time being function of at least a parameter of the apparatus.

In a 22^(nd) aspect according to the previous aspect, the at least oneparameter is chosen in the group including a volume of the secondarychamber (4) of the filtration unit (2), dialysis fluid flow rate, bloodflow rate, filtration unit permeability.

In a 23^(rd) aspect according to the previous 21^(st) or 22^(nd)aspects, during the step of determining reaching of stable conditions,the control unit (12) is configured to prevent changes in the dialysisfluid flow rate, particularly the control unit (12) is also configuredto prevent changes in the blood flow rate and/or in the ultrafiltrationrate.

In a 24^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to measure a conductivity value of thedialysate and to compensate the measured initial conductivity value ofthe dialysate for the effect of the electrically neutral substance, inparticular said electrically neutral substances include urea andglucose.

In a 25^(th) aspect according to the previous aspect, the control unit(12) is configured to compensate the measured initial conductivity valueof the dialysate as a function of the concentration of at least asubstance in the dialysis fluid, said substance being particularlyglucose.

In a 26^(th) aspect according to the previous 24^(th) or 25^(th)aspects, the control unit is configured to compensate the measuredinitial conductivity value of the dialysate as a function of at leastone flow rate, in particular the dialysate flow rate at the outlet ofthe secondary chamber (4).

In a 27^(th) aspect according to anyone of the previous aspects from the24^(th) to the 26^(th), the control unit is configured to compensate themeasured initial conductivity value of the dialysate as a function of atleast an efficiency parameter of the filtration unit (2), in particulara clearance of the filtration unit (2), optionally the urea clearance.

In a 28^(th) aspect according to anyone of the previous aspects from the24^(th) to the 27^(th), the control unit is configured to compensate themeasured initial conductivity value of the dialysate as a function of anestimated plasma concentration of at least a substance chosen in thegroup including glucose and urea, in particular as a function of theestimated plasma concentration of both glucose and urea.

In a 29^(th) aspect according to anyone of the previous aspects from the24^(th) to the 28^(th), the control unit is configured to compensate themeasured initial conductivity value of the dialysate using the followingformula (III):

$\begin{matrix}{\kappa_{0,{do}} = \frac{\kappa_{do}}{\begin{matrix}\left( {1 - {\gamma_{g}\left( {c_{{di},g} + {\frac{f_{g,K_{B}}K_{u}}{Q_{do}}\left( {\frac{c_{p,g}}{f_{pw}} - c_{{di},g}} \right)}} \right)}} \right. \\\left( {1 - {\gamma_{u}\frac{K_{u}}{Q_{do}}\frac{c_{p,u}}{f_{pw}}}} \right)\end{matrix}}} & ({III})\end{matrix}$

wherein:

κ_(do) Dialysate conductivity after filtration unit; Q_(do) Dialysateflow rate at the filtration unit outlet; K_(u) Filtration unit clearancefor urea; c_(di,g) Dialysis fluid concentration of glucose; c_(p,g)Pre-dialysis concentration of glucose in plasma; c_(p,u) Pre-dialysisconcentration of urea in plasma; f_(pw) Plasma water fraction, i.e. thepart of plasma that is pure water; f_(g,KB) Glucose clearance fraction,i.e. the relative glucose clearance compared to urea clearance; □_(0,do)Dialysate fluid conductivity at the filtration unit outlet for a pureelectrolyte solution (with conductivity compensated for the influence ofglucose and urea); □_(g) Conductivity correction term for glucose; □_(u)Conductivity correction term for urea;

In a 30^(th) aspect according to anyone of the previous aspects, thecontrol unit (12) is configured to compensate an initial conductivity ofthe dialysis fluid for the effect of the electrically neutralsubstances, in particular said electrically neutral substances includeglucose.

In a 31^(st) aspect according to the previous aspect, the control unit(12) is configured to compensate the initial conductivity of thedialysis fluid as a function of the concentration of at least asubstance in the dialysis fluid, said substance being particularlyglucose.

In a 32^(nd) aspect according to anyone of the previous 30^(th) or31^(st) aspects, the control unit is configured to compensate theinitial conductivity of the dialysis fluid using the following formula(IV):

$\begin{matrix}{\kappa_{0,{di}} = \frac{\kappa_{di}}{1 - {\gamma_{g}c_{{di},g}}}} & ({IV})\end{matrix}$

wherein:

κ_(di) Dialysis fluid conductivity upstream the filtration unit;c_(di,g) Dialysis fluid concentration of glucose; □_(0,di) Dialysisfluid conductivity at the filtration unit inlet for a pure electrolytesolution (with conductivity compensated for the influence of glucose, ifpresent); □_(g) Conductivity correction term for glucose;

In a 33^(rd) aspect according to anyone of the previous aspects, oncethe diffusion process in the filtration unit (2) reaches stableconditions, the control unit (12) is configured to determine at least aninitial conductivity of the dialysis fluid upstream said secondarychamber (4), said determining being executed either by receiving thedialysis fluid conductivity set value or by receiving a signal from asensor for measuring a conductivity-related value of the dialysis fluidin the dialysis fluid supply line (8).

In a 34^(th) aspect according to the previous aspect, the control unit(12) is configured to determine the initial conductivity of the dialysisfluid and the initial conductivity of the dialysate substantially at thesame time.

In a 35^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the plasma conductivity as afunction of at least one flow rate, in particular said flow rate beingchosen in the group including the dialysate flow rate at the outlet ofthe secondary chamber (4) and the blood flow rate in the blood lines (6,7).

In a 36^(th) aspect according to the previous aspect, the control unitis configured to calculate the plasma conductivity as a function of thedialysate flow rate at the outlet of the secondary chamber (4) and theblood flow rate in the blood lines (6, 7).

In a 37^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the plasma conductivity as afunction of at least an efficiency parameter of the filtration unit (2),in particular a clearance of the filtration unit (2), optionally theurea clearance.

In a 38^(th) aspect according to anyone of the previous aspects from the24^(th) to 29^(th), the control unit is configured to calculate theplasma conductivity as a function of at least a compensated initialconductivity of the dialysate.

In a 39^(th) aspect according to anyone of the previous aspects from the30^(th) to 32^(nd), the control unit is configured to calculate theplasma conductivity as a function of at least a compensated conductivityof the dialysis fluid in the dialysis supply line (8).

In a 40^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the plasma conductivityaccording to the following formula (V):

$\begin{matrix}{\kappa_{p,1}^{\prime} = {\kappa_{0,{do}} + {\frac{Q_{do}}{Q_{Bset}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}} & (V)\end{matrix}$

wherein:

κ_(p,l) Plasma conductivity first estimate; Q_(do) Dialysate flow rateat the filtration unit outlet; Q_(bset) Set blood flow rate at thefiltration unit inlet; □_(0,di) Dialysis fluid conductivity at thefiltration unit inlet for a pure electrolyte solution; □_(0,do)Dialysate conductivity at the filtration unit outlet for a pureelectrolyte solution;

In a 41^(st) aspect according to anyone of the previous aspects, thecontrol unit is configured to calculate the plasma conductivityaccording to the following formula (VI):

$\begin{matrix}{\kappa_{p,1}^{''} = {\kappa_{0,{di}} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}} & ({VI})\end{matrix}$

wherein:

κ_(p,l) Plasma conductivity first estimate; Q_(do) Dialysate fluid flowrate at the filtration unit outlet; K_(u) Filtration unit clearance forurea; □_(0,di) Dialysis fluid conductivity at the filtration unit inletfor a pure electrolyte solution; □_(0,do) Dialysate conductivity at thefiltration unit outlet for a pure electrolyte solution;

In a 42^(nd) aspect according to anyone of the 37^(th) or 41^(st)aspect, the control unit is configured to calculate the urea clearanceas a function of at least one flow rate chosen in the group includingthe blood water flow rate, the blood flow rate, and the dialysis fluidflow rate at the inlet of the secondary chamber (4).

In a 43^(rd) aspect according to the previous aspect, the control unitis configured to calculate the urea clearance according to the followingformula (VII):

$\begin{matrix}{K_{u} = {Q_{bw}Q_{di}\frac{1 - e^{{KoA}({\frac{1}{Q_{di}}\frac{1}{Q_{bw}}})}}{Q_{di} - {Q_{bw}e^{{KoA}({\frac{1}{Q_{di}}\frac{1}{Q_{bw}}})}}}}} & ({VII})\end{matrix}$

wherein:

Q_(di) Dialysis fluid flow rate at the filtration unit inlet; Q_(bw)Real blood water flow rate at the filtration unit inlet; K_(u)Filtration unit clearance for urea; K_(oA) Urea mass transfercoefficient of the filtration unit;

In a 44^(th) aspect according to anyone of the previous aspects, aftercalculating the initial plasma conductivity, the control unit isconfigured to drive the regulating means (10) to change the compositionof the dialysis fluid to reach a dialysis fluid conductivitysubstantially equal to the calculated initial plasma conductivity.

In a 45^(th) aspect according to anyone of the previous aspects,immediately after calculating the initial plasma conductivity, thecontrol unit is configured to drive the regulating means (10) to changethe composition of the dialysis fluid and to set the dialysis fluidconductivity substantially equal to the calculated plasma conductivity.

In a 46^(th) aspect according to the previous aspect, after setting thedialysis fluid conductivity substantially equal to the calculated plasmaconductivity, the control unit is configured to execute a secondcalculating step, based on a second determined initial conductivity ofthe dialysate and on a second corresponding conductivity of the dialysisfluid in the supply line (8), of a second estimate of the initial plasmaconductivity, said calculating the second estimate being performedmaintaining the dialysis fluid conductivity substantially constant andsubstantially equal to the calculated plasma conductivity.

In a 47^(th) aspect according to anyone of the previous aspects, aftercalculating the second estimate of the initial plasma conductivity, thecontrol unit is configured to drive the regulating means (10) to changethe composition of the dialysis fluid and to set the dialysis fluidconductivity substantially equal to said second estimate.

In a 48^(th) aspect according to anyone of the previous 46^(th) or47^(th) aspects, the calculation of the second estimate of the plasmaconductivity is executed according to anyone of the aspects from the35^(th) to 43^(rd).

In a 49^(th) aspect according to anyone of the previous aspects, thecontrol unit is configured to drive the regulating means as a functionof the calculated plasma conductivity to change the dialysis fluidconductivity.

In a 50^(th) aspect according to anyone of the previous aspects, thecontrol unit is programmed to allow selection of at least one treatmentmode chosen in the group including isotonic dialysis, isonatremicdialysis, and isonatrikalemic dialysis, the control unit is configuredto drive the regulating means as a function of the calculated plasmaconductivity and of the chosen treatment mode to set either a desireddialysis fluid inlet conductivity or a desired dialysis fluid inletsubstance concentration, in particular said substance being sodium.

In a 51^(st) aspect according to the previous aspect, the control unitis programmed to keep the desired dialysis fluid inlet conductivitysubstantially constant throughout the remainder of the treatment.

In a 52^(nd) aspect according to the 5^(th) aspect, the parameter valueis a conductivity value of the dialysis fluid.

In a 53^(rd) aspect according to anyone of the previous aspects, thesetting of the parameter value in the dialysis fluid includes thesub-step of calculating the parameter value as a function of a maincontribution term based on a blood parameter and as a function of anadjustment contribution term based on a concentration of at least asubstance in the dialysis fluid chosen in the group includingbicarbonate, potassium, acetate, lactate, citrate, magnesium, calcium,and phosphate, said blood parameter being the plasma conductivity or aplasma conductivity-related of the blood in the extracorporeal bloodcircuit.

In a 54^(th) aspect according to the previous aspect, the control unitis configured to calculate the adjustment contribution term based on theconcentration of two or more substances in the dialysis fluid chosen inthe group including bicarbonate, potassium, acetate, lactate, citrate,in particular as a function of the concentration of at least three ofsaid substances, optionally as a function of the concentration ofbicarbonate, potassium, and acetate in the dialysis fluid.

In a 55^(th) aspect according to the 53^(rd) or 54^(th) aspect, thecontrol unit is configured to calculate the adjustment contribution termas a function of the difference in concentration of at least a substancein the dialysis fluid and the same substance in the blood plasma.

In a 56^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 55^(th), the control unit is configured to calculate theadjustment contribution term as a function of the difference inconcentration of at least a substance in the dialysis fluid and the samesubstance in the plasma, said substance being chosen in the groupincluding bicarbonate, potassium, acetate, lactate, and citrate, inparticular as a function of the difference in concentration of at leasttwo of said substances, optionally as a function of the difference inconcentration of bicarbonate, potassium, citrate, and acetate in thedialysis fluid and plasma.

In a 57^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 56^(th), the blood parameter is the plasma conductivity,or the concentration of at least a substance in the blood, saidsubstance being in particular sodium.

In a 58^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 57^(th), the parameter of the dialysis fluid is theconductivity of the dialysis fluid, or the concentration of at least asubstance in the dialysis fluid, said substance being in particularsodium.

In a 59^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 58^(th), the blood parameter is the plasma conductivityand the parameter of the dialysis fluid is the conductivity of thedialysis fluid.

In a 60^(th) aspect according to anyone of the previous aspects from the53^(rd) to 59^(th), the blood parameter is the concentration of at leasta substance in the blood, said substance being in particular sodium, andthe parameter of the dialysis fluid is the concentration of at least asubstance in the dialysis fluid, said substance being in particularsodium.

In a 61^(st) aspect according to anyone of the previous aspects from the53^(st) to the 60^(th), the blood parameter is the concentration of atleast a substance in the blood, and the parameter of the dialysis fluidis the concentration of at least the same substance in the dialysisfluid.

In a 62^(nd) aspect according to anyone of the previous aspects from the53^(rd) to the 61^(st), the main contribution term is dimensionally aconcentration of a substance in a fluid.

In a 63^(st) aspect according to anyone of the previous aspects from the53^(st) to the 62^(nd), the main contribution term is a dialysis fluidconcentration of sodium at an isoconductive state, i.e. when thedialysis fluid conductivity substantially matches the plasmaconductivity.

In a 64^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 63^(rd), the main contribution term affects the dialysisfluid parameter value for at least 80% of the parameter value, theadjustment contribution term contributes to the dialysis fluid parametervalue for less than 15% of the parameter value.

In a 65^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 64^(th), the sub-step of calculating the parameter valueas a function of the main contribution term and the adjustmentcontribution term is a sub-step of calculating an algebraic sum of atleast the main contribution term and the adjustment contribution termand particularly the adjustment contribution term is dimensionally aconcentration of a substance in a fluid.

In a 66^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 65^(th), the adjustment contribution term is the sodiumconcentration set point adjustment relative to an isoconductive state toprovide a treatment chosen in the group including isotonic dialysis,isonatremic dialysis, and isonatrikalemic dialysis.

In a 67^(th) aspect according to anyone of the previous aspects from the53^(st) to the 66^(th), the main contribution term affects (contributesto) the dialysis fluid parameter value for at least 90% of the parametervalue, the adjustment contribution term contributing to the dialysisfluid parameter value for less than 10% of the parameter value.

In a 68^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 67^(th), the control unit drives the regulating means(10) for regulating the conductivity or the concentration of at least asubstance in the dialysis fluid, the control unit setting the parametervalue for the dialysis fluid in the dialysis supply line (8) at thecalculated set point.

In a 69^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 68^(th), the regulating means (10) regulates theconcentration of at least a substance in the dialysis fluid, inparticular an ionic substance, such as sodium.

In a 70^(th) aspect according to anyone of the previous aspects from the53^(st) to the 69^(th), the control unit drives the regulating means(10) for regulating the sodium concentration in the dialysis fluid toset the parameter value for the dialysis fluid in the dialysis supplyline (8) at the calculated set point.

In a 71^(st) aspect according to anyone of the previous aspects from the53^(rd) to the 70^(th), the control unit is configured to calculate theadjustment contribution term as a function of the molar conductivitiesof at least a substance in the dialysis fluid chosen in the groupincluding sodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodiumacetate (NaCH₃COO), potassium chloride (KCl), lactate, and trisodiumcitrate (Na₃C₆H₅O₇), in particular as a function of the molarconductivities of at least two of said substances, in more detail as afunction of the molar conductivities of at least three of saidsubstances, optionally as a function of the molar conductivities ofsodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodium acetate(NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl).

In a 72^(nd) aspect according to anyone of the previous aspects from the53^(rd) to the 71^(st), the control unit is configured to calculate theadjustment contribution term as a function of a difference between twomolar conductivities.

In a 73^(st) aspect according to anyone of the previous aspects from the53^(rd) to the 72^(nd), the control unit is configured to calculate theadjustment contribution term as a function of a difference between afirst molar conductivity of a substance chosen in the group includingsodium bicarbonate (NaHCO₃), sodium acetate (NaCH₃COO), trisodiumcitrate (Na₃C₆H₅O₇), and potassium chloride (KCl), and a molarconductivity of sodium chloride (NaCl).

In a 74^(th) aspect according to anyone of the previous aspects from the53^(st) to the 73^(rd), the control unit is configured to calculate theadjustment contribution term as a function of a difference between amolar conductivity of sodium bicarbonate (NaHCO₃), and a molarconductivity of sodium chloride (NaCl).

In a 75^(th) aspect according to anyone of the previous aspects from the53^(st) to the 74^(th), the control unit is configured to calculate theadjustment contribution term as a function of a difference between amolar conductivity of sodium acetate (NaCH₃COO), and a molarconductivity of sodium chloride (NaCl).

In a 76^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 75^(th), the control unit is configured to calculate theadjustment contribution term as a function of a difference between amolar conductivity of trisodium citrate (Na₃C₆H₅O₇), and a molarconductivity of sodium chloride (NaCl).

In a 77^(th) aspect according to anyone of the previous aspects from the53^(st) to the 76^(th), the control unit is configured to calculate theadjustment contribution term as a function of a difference between amolar conductivity of potassium chloride (KCl), and a molar conductivityof sodium chloride (NaCl).

In a 78^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 77^(th), the control unit is configured to calculate theadjustment contribution term as a function of an estimated plasma waterconcentration of at least a substance chosen in the group includingbicarbonate, potassium, acetate, lactate, and citrate, in particular asa function of the estimated plasma water concentration of at least twoof said substances, in more detail as a function of the estimated plasmawater concentration of at least three of said substances, optionally asa function of the estimated plasma water concentration of bicarbonate,potassium, citrate, and acetate.

In a 79^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 78^(th), the estimated plasma water concentration of atleast a substance chosen in the group including bicarbonate, potassium,citrate, and acetate is the mean pre-dialysis values of thecorresponding substance for large patient populations or historical dataof the corresponding substance for the individual patient or theoreticalvalues of the corresponding substance or measured values of thecorresponding substance.

In a 80^(th) aspect according to the 78^(th) or 79^(th) aspects, theestimated plasma water concentration is adjusted by a respective,preferably fixed, adjusting factor taking account of the Donnan effect.

In a 81^(st) aspect according to anyone of the previous aspects from the53^(st) to the 80^(th), the control unit is configured to calculate theadjustment contribution term as an algebraic sum of at least twocomponents, a first component being function of the difference, inparticular weighted difference, in concentration of at least a substancein the dialysis fluid and the same substance in the blood plasma, thesecond component being function of the difference, in particularweighted difference, in concentration of at least a second substance inthe dialysis fluid and the same second substance in the blood plasma.

In an 82^(nd) aspect according to anyone of the previous aspects fromthe 53^(st) to the 81^(st), the control unit is configured to calculatethe adjustment contribution term as an algebraic sum of at least threecomponents, a first component being function of the difference, inparticular weighted difference, in concentration of at least a substancein the dialysis fluid and the same substance in the blood plasma, thesecond component being function of the difference, in particularweighted difference, in concentration of at least a second substance inthe dialysis fluid and the same second substance in the blood plasma,the third component being function of the difference, in particularweighted difference, in concentration of at least a third substance inthe dialysis fluid and the same third substance in the blood plasma.

In an 83^(st) aspect according to anyone of the previous aspects fromthe 53^(st) to the 82^(nd), the control unit is configured to calculatethe adjustment contribution term as an algebraic sum of at least twocomponents, a first component being function of a concentration of atleast a substance in the dialysis fluid and/or in the blood plasma, asecond component being function of a concentration of at least a secondsubstance in the dialysis fluid and/or in the blood plasma.

In an 84^(th) aspect according to anyone of the previous aspects fromthe 53^(rd) to the 83^(rd), the control unit is configured to calculatethe adjustment contribution term as an algebraic sum of at least threecomponents, a first component being function of a concentration of atleast a substance in the dialysis fluid and/or in the blood plasma, asecond component being function of a concentration of at least a secondsubstance in the dialysis fluid and/or in the blood plasma, a thirdcomponent being function of a concentration of at least a thirdsubstance in the dialysis fluid and/or in the blood plasma.

In an 85^(th) aspect according to anyone of the previous aspects fromthe 81^(st) to the 84^(th), said substance is chosen in the groupincluding bicarbonate anions (HCO₃ ⁻), acetate anions (CH₃COO⁻),citrate, and potassium ions (K⁺).

In an 86^(th) aspect according to anyone of the previous aspects fromthe 53^(rd) to the 85^(th), the control unit is configured to calculatethe adjustment contribution term as a function of at least one flowrate, in particular the spent dialysis fluid flow rate at the outlet ofthe secondary chamber (4).

In an 87^(th) aspect according to anyone of the previous aspects fromthe 53^(st) to the 86^(th), the control unit is configured to calculatethe adjustment contribution term as a function of at least an efficiencyparameter of the filtration unit (2), in particular a clearance of thefiltration unit (2), optionally the urea clearance and/or the citrateclearance.

In an 88^(th) aspect according to anyone of the previous aspects fromthe 53^(st) to the 87^(th), the control unit is configured to calculatethe adjustment contribution term as a function of at least a ratiobetween one flow rate, in particular the spent dialysis fluid flow rateat the outlet of the secondary chamber (4), and an efficiency parameterof the filtration unit (2), in particular a clearance of the filtrationunit (2), optionally the urea clearance and/or the citrate clearance.

In an 89^(th) aspect according to anyone of the previous aspects fromthe 53^(rd) to the 88^(th), the control unit is configured to calculatethe adjustment contribution term as an algebraic sum of at least two,and particularly three or four or five, components, one component beinga function of at least a ratio between one flow rate, in particular thespent dialysis fluid flow rate at the outlet of the secondary chamber(4), and an efficiency parameter of the filtration unit (2), inparticular a clearance of the filtration unit (2), optionally the ureaclearance and/or the citrate clearance.

In a 90^(th) aspect according to anyone of the previous aspects from the53^(st) to the 89^(th), the control unit (12) is programmed forcalculating the blood parameter.

In a 91^(st) aspect according to anyone of the previous aspects from the53^(rd) to the 90^(th), the control unit (12) is programmed forreceiving as an input the blood parameter.

In a 92^(nd) aspect according to anyone of the previous aspects from the53^(st) to the 91^(st), the control unit (12) is programmed for storingin a memory said value representative of the parameter of the blood insaid blood lines, said value representative of the parameter of theblood being not calculated by the control unit.

In a 93^(rd) aspect according to anyone of the previous aspects from the53^(rd) to the 92^(nd), the adjustment contribution term has a negativevalue.

In a 94^(th) aspect according to anyone of the previous aspects from the53^(st) to the 93^(rd), the adjustment contribution term is:

$\begin{matrix}{c_{{di},{Na},{isotonic},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right)\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{{rest}1} + \kappa_{{rest}2}} \right)}} \right)}} & ({VIII})\end{matrix}$

wherein:

C_(di,Na,isotonic,adj) Sodium concentration set point adjustment(relative to isoconductive state) required to provide isotonic dialysisM _(κ) _(NaHCO3) Is the molar conductivity of sodium bicarbonate(NaHCO₃) M _(κ) _(NaCl) Is the molar conductivity of sodium chloride(NaCl) M _(κ) _(NaAc) Is the molar conductivity of sodium acetate(NaCH₃COO) M _(κ) _(KCl) Is the molar conductivity of potassium chloride(KCl) □_(rest1) Is the conductivity contribution from lesser solutes 1□_(rest2) Is the conductivity contribution from lesser solutes 2c_(di,HCO3) Is the dialysis fluid concentration of bicarbonate c_(di,K)Is the dialysis fluid concentration of potassium c_(di,Ac) Is thedialysis fluid concentration of acetate c_(pw,HCO3) Is the estimated ormeasured pre-dialysis concentration of bicarbonate anions (HCO₃ ⁻) inplasma water c_(pw,Ac) Is the estimated or measured pre-dialysisconcentration of acetate anions (CH₃COO⁻) in plasma water c_(pw,K) Isthe estimated or measured pre-dialysis concentration of potassium ions(K⁺) in plasma water Qdo Is the dialysate flow rate at dialyzer outletKu Is the dialyzer clearance for urea α Is the Donnan factor

In a 95^(th) aspect according to anyone of the previous aspects from the53^(st) to the 93^(st), the adjustment contribution term is:

$\begin{matrix}{c_{{di},{Na},{isoNa},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}{M_{\kappa_{KCl}}\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)}} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}3}}} \right)}} & ({IX})\end{matrix}$

wherein:

C_(di,Na,isoNa,adj) Sodium concentration set point adjustment (relativeto isoconductive state) required to provide isonatremic dialysis M _(κ)_(NaHCO3) Is the molar conductivity of sodium bicarbonate (NaHCO₃) M_(κ) _(NaCl) Is the molar conductivity of sodium chloride (NaCl) M _(κ)_(NaAc) Is the molar conductivity of sodium acetate (NaCH₃COO) M _(κ)_(KCl) Is the molar conductivity of potassium chloride (KCl) □_(rest3)Is the conductivity contribution from lesser solutes 3 c_(di,HCO3) Isthe dialysis fluid concentration of bicarbonate anions (HCO₃ ⁻) c_(di,K)Is the dialysis fluid concentration of potassium ions (K⁺) c_(di,Ac) Isthe dialysis fluid concentration of acetate anions (CH₃COO⁻) c_(pw,HCO3)Is the estimated or measured pre-dialysis concentration of bicarbonateanions (HCO₃ ⁻) in plasma water c_(pw,Ac) Is the estimated or measuredpre-dialysis concentration of acetate anions (CH₃COO⁻) in plasma waterc_(pw,K) Is the estimated or measured pre-dialysis concentration ofpotassium ions (K⁺) in plasma water Qdo Is the dialysate flow rate atdialyzer outlet Ku Is the dialyzer clearance for urea α Is the Donnanfactor

In a 96^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 93^(rd), the adjustment contribution term is:

$\begin{matrix}{c_{{di},{Na},{{isoNa} + K},{adj}} = {{- \frac{1}{M_{\kappa_{NaC1}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right)\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}3}}} \right)}} & (X)\end{matrix}$

wherein:

C_(di,Na,isoNa+K,adj) Sodium concentration set point adjustment(relative to isoconductive state) required to provide isonatrikalemicdialysis M _(κ) _(NaHCO3) Is the molar conductivity of sodiumbicarbonate (NaHCO₃) M _(κ) _(NaCl) Is the molar conductivity of sodiumchloride (NaCl) M _(κ) _(NaAc) Is the molar conductivity of sodiumacetate (NaCH₃COO) M _(κ) _(KCl) Is the molar conductivity of potassiumchloride (KCl) □_(rest3) Is the conductivity contribution from lessersolutes 3 c_(di,HCO3) Is the dialysis fluid concentration of bicarbonateanions (HCO₃ ⁻) c_(di,K) Is the dialysis fluid concentration ofpotassium ions (K⁺) c_(di,Ac) Is the dialysis fluid concentration ofacetate anions (CH₃COO⁻) c_(pw,HCO3) Is the estimated or measuredpre-dialysis concentration of bicarbonate anions (HCO₃ ⁻) in plasmawater c_(pw,Ac) Is the estimated or measured pre-dialysis concentrationof acetate anions (CH₃COO⁻) in plasma water c_(pw,K) Is the estimated ormeasured pre-dialysis concentration of potassium ions (K⁺) in plasmawater Qdo Is the dialysate flow rate at dialyzer outlet Ku Is thedialyzer clearance for urea α Is the Donnan factor

In a 97^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 93^(rd), the adjustment contribution term is:

$\begin{matrix}{c_{{di},{Na},{isotonic},{adj}} = {{- \frac{1}{M_{\kappa_{NaC1}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right){\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)++}\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{{Na}_{3}{Cit}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\alpha^{- 3}} + {0.125\alpha^{- 2}} + {0.706\alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{{di},{{Na}_{3}{Cit}}}} \right)++}\frac{Q_{do}}{K_{u}}\left( {\kappa_{{rest}1} + \kappa_{{rest}2}} \right)}} \right)}} & ({XI})\end{matrix}$

wherein:

C_(di,Na,isotonic,adj) Sodium concentration set point adjustment(relative to isoconductive state) required to provide isotonic dialysisM _(κ) _(NaHCO3) Is the molar conductivity of sodium bicarbonate(NaHCO₃) M _(κ) _(NaCl) Is the molar conductivity of sodium chloride(NaCl) M _(κ) _(NaAc) Is the molar conductivity of sodium acetate(NaCH₃COO) M _(κ) _(KCl) Is the molar conductivity of potassium chloride(KCl) M _(Na) ₃ _(Cit) Is the molar conductivity of trisodium citrate(Na₃C₆H₅O₇) □_(rest1) Is the conductivity contribution from lessersolutes 1 □_(rest2) Is the conductivity contribution from lesser solutes2 c_(di,HCO3) Is the dialysis fluid concentration of bicarbonate anions(HCO₃ ⁻) c_(di,K) Is the dialysis fluid concentration of potassium ions(K⁺) c_(di,Ac) Is the dialysis fluid concentration of acetate anions(CH₃COO⁻) c_(di,Na) ₃ _(Cit) Is the dialysis fluid concentration oftotal citrate c_(pw,HCO3) Is the estimated or measured pre-dialysisconcentration of bicarbonate anions (HCO₃ ⁻) in plasma water c_(pw,Ac)Is the estimated or measured pre-dialysis concentration of acetateanions (CH₃COO⁻) in plasma water c_(pw,K) Is the estimated or measuredpre-dialysis concentration of potassium ions (K⁺) in plasma waterc_(pw,Na) ₃ _(Cit) Is the estimated or measured pre-dialysisconcentration of total citrate in plasma water Qdo Is the dialysate flowrate at dialyzer outlet Ku Is the dialyzer clearance for urea K_(b)_(Cit) Is the dialyzer clearance for citrate α Is the Donnan factor

In a 98^(th) aspect according to anyone of the previous aspects from the53^(rd) to the 93^(rd), the adjustment contribution term is:

$\begin{matrix}{c_{{di},{Na},{isoNa},{adj}} = {{- \frac{1}{M_{\kappa_{NaC1}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{{Na}_{3}{Cit}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\alpha^{- 3}} + {0.125\alpha^{- 2}} + {0.706\alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{{di},{{Na}_{3}{Cit}}}} \right)++}{M_{\kappa_{KCl}}\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)}} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}3}}} \right)}} & ({XII})\end{matrix}$

wherein:

C_(di,Na,isoNa,adj) Sodium concentration set point adjustment (relativeto isoconductive state) required to provide isonatremic dialysis M _(κ)_(NaHCO3) Is the molar conductivity of sodium bicarbonate (NaHCO₃) M_(κ) _(NaCl) Is the molar conductivity of sodium chloride (NaCl) M _(κ)_(NaAc) Is the molar conductivity of sodium acetate (NaCH₃COO) M _(κ)_(KCl) Is the molar conductivity of potassium chloride (KCl) M _(Na) ₃_(Cit) Is the molar conductivity of trisodium citrate (Na₃C₆H₅O₇)□_(rest3) Is the conductivity contribution from lesser solutes 3c_(di,HCO3) Is the dialysis fluid concentration of bicarbonate anions(HCO₃ ⁻) c_(di,K) Is the dialysis fluid concentration of potassium ions(K⁺) c_(di,Ac) Is the dialysis fluid concentration of acetate anions(CH₃COO⁻) c_(di,Na) ₃ _(Cit) Is the dialysis fluid concentration oftotal citrate c_(pw,HCO3) Is the estimated or measured pre-dialysisconcentration of bicarbonate anions (HCO₃ ⁻) in plasma water c_(pw,Ac)Is the estimated or measured pre-dialysis concentration of acetateanions (CH₃COO⁻) in plasma water c_(pw,K) Is the estimated or measuredpre-dialysis concentration of potassium ions (K⁺) in plasma waterc_(pw,Na) ₃ _(Cit) Is the estimated or measured pre-dialysisconcentration of total citrate in plasma water Qdo Is the dialysate flowrate at dialyzer outlet Ku Is the dialyzer clearance for urea K_(b)_(Cit) Is the dialyzer clearance for citrate α Is the Donnan factor

In a 99^(th) aspect according to anyone of the previous aspects from the53^(st) to the 93^(rd), the adjustment contribution term is:

$\begin{matrix}{c_{{di},{Na},{{isoNa} + K},{adj}} = {{- \frac{1}{M_{\kappa_{NaC1}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{{Na}_{3}{Cit}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\alpha^{- 3}} + {0.125\alpha^{- 2}} + {0.706\alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{{di},{{Na}_{3}{Cit}}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right)\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}3}}} \right)}} & ({XIII})\end{matrix}$

wherein:

C_(di,Na,isoNa+K,adj) Sodium concentration set point adjustment(relative to isoconductive state) required to provide isonatrikalemicdialysis M _(κ) _(NaHCO3) Is the molar conductivity of sodiumbicarbonate (NaHCO₃) M _(κ) _(NaCl) Is the molar conductivity of sodiumchloride (NaCl) M _(κ) _(NaAc) Is the molar conductivity of sodiumacetate (NaCH₃COO) M _(κ) _(KCl) Is the molar conductivity of potassiumchloride (KCl) M _(Na) ₃ _(Cit) Is the molar conductivity of trisodiumcitrate (Na₃C₆H₅O₇) □_(rest3) Is the conductivity contribution fromlesser solutes 3 c_(di,HCO3) Is the dialysis fluid concentration ofbicarbonate anions (HCO₃ ⁻) c_(di,K) Is the dialysis fluid concentrationof potassium ions (K⁺) C_(di,Ac) Is the dialysis fluid concentration ofacetate anions (CH₃COO⁻) c_(di,Na) ₃ _(Cit) Is the dialysis fluidconcentration of total citrate c_(pw,HCO3) Is the estimated or measuredpre-dialysis concentration of bicarbonate anions (HCO₃ ⁻) in plasmawater c_(pw,Ac) Is the estimated or measured pre-dialysis concentrationof acetate anions (CH₃COO⁻) in plasma water c_(pw,K) Is the estimated ormeasured pre-dialysis concentration of potassium ions (K⁺)in plasmawater c_(pw,Na) ₃ _(Cit) Is the estimated or measured pre-dialysisconcentration of total citrate in plasma water Qdo Is the dialysate flowrate at dialyzer outlet Ku Is the dialyzer clearance for urea K_(b)_(Cit) Is the dialyzer clearance for citrate α Is the Donnan factor

In a 100^(th) aspect according to the previous aspects, the setting ofthe second parameter value in the dialysis fluid includes the sub-stepof calculating the parameter value as a function of the maincontribution term, the adjustment contribution term and a compensationcontribution term.

In a 101^(st) aspect according to the previous aspect, the compensationcontribution term is dimensionally a concentration of a substance in afluid.

In a 102^(nd) aspect according to the previous two aspects, the sub-stepof calculating the parameter value as a function of the maincontribution term, the adjustment contribution term and the compensationcontribution term is a sub-step of calculating an algebraic sum of atleast the main contribution term, the adjustment contribution term, andthe compensation contribution term.

In a 103^(st) aspect according to the previous three aspects, thecompensation contribution term is a sodium compensation term tocompensate for occurred unintended sodium transfers during treatment.

In a 104^(th) aspect according to the previous four aspects, thecompensation contribution term is a sodium compensation term tocompensate for unintended sodium transfers occurred during calculationof said value representative of the parameter of the blood in said bloodlines, particularly at the start of the treatment.

In a 105^(th) aspect according to the previous aspect, the compensationcontribution term has generally a negative value.

In a 106^(th) aspect according to the previous six aspects, the controlunit (12) is further configured, during a monitoring phase, tore-determine the blood parameter, the monitoring phase occurring apredetermined number of times during the treatment, at each monitoringphase an unintended net transfer of a substance, e.g. sodium, occursthrough the semipermeable membrane (5), the compensation contributionterm is a sodium compensation term to compensate for occurred unintendedsodium transfers during the monitoring phase.

In a 107^(th) aspect according to the previous seven aspects, thecompensation contribution term for the unintended substance transfer iscalculated for distributing a compensation for the substance during theremaining treatment time.

In a 108^(th) aspect according to the previous eight aspects, thecompensation contribution term is a function of the remaining treatmenttime, i.e. total treatment time (T) minus elapsed treatment time(t_(i)), in particular is a function of 1/(T−t_(i)).

In a 109^(th) aspect according to the previous nine aspects, thecompensation contribution term is a function of the difference betweenthe calculated substance, e.g. sodium, set point(c_(di,Na,set,isotonic); c_(di,Na,set,isoNa); c_(di,Na,set,isoNa+K)) andthe actual dialysis fluid same substance, e.g. sodium, concentration setpoint (c_(di,Na,set,actual)) used during treatment.

In a 110^(th) aspect according to the previous ten aspects, thecompensation contribution term is calculated according to the followingformula:

$\begin{matrix}{\sum\limits_{i}{\frac{1}{T - t_{i}}{\int\limits_{t_{i}}^{t_{i} + {\Delta t_{i}}}{\left( {c_{{di},{Na},{set}} - c_{{di},{Na},{actual},i}} \right){dt}}}}} & ({XIV})\end{matrix}$

wherein

c_(di,Na,set,actual) is the actual dialysis fluid sodium concentrationset point used during the treatment;

c_(di,Na,set), is the calculated sodium set point which may correspondto either dialysis fluid concentration of sodium ions (Na⁺) to provideisotonic dialysis c_(di,Na,set,isotonic) or dialysis fluid concentrationof sodium ions (Na⁺) to provide isonatremic dialysis c_(di,Na,set,isoNa)or dialysis fluid concentration of sodium ions (Na⁺) to provideisonatrikalemic dialysis c_(di,Na,set,isoNa+K);

T is the total treatment time; and

t_(i) is the elapsed treatment time.

In a 111^(th) aspect according to the previous eleven aspects, thesecond parameter value in the dialysis fluid is calculated according tothe following relation:

$\begin{matrix}{c_{{di},{Na},{set},{compensated}} = {c_{{di},{Na},{set}} + {\sum\limits_{i}{\frac{1}{T - t_{i}}{\int\limits_{t_{i}}^{t_{i}\Delta t_{i}}{\left( {c_{{di},{Na},{set}} - c_{{di},{Na},{actual},i}} \right){dt}}}}}}} & ({XV})\end{matrix}$

wherein

c_(di,Na,set,actual) is the actual dialysis fluid sodium concentrationset point used during the treatment;

c_(di,Na,set), is the calculated sodium set point which may correspondto either dialysis fluid concentration of sodium ions (Na⁺) to provideisotonic dialysis c_(di,Na,set,isotonic) or dialysis fluid concentrationof sodium ions (Na⁺) to provide isonatremic dialysis c_(di,Na,set,isoNa)or dialysis fluid concentration of sodium ions (Na⁺) to provideisonatrikalemic dialysis c_(di,Na,set,isoNa+K);

T is the total treatment time; and

t_(i) is the elapsed treatment time.

Further characteristics and advantages of the present invention willbetter emerge from the detailed description that follows of at least anembodiment of the invention, illustrated by way of non-limiting examplein the accompanying figures of the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The description will now follow, with reference to the appended figures,provided by way of non-limiting example, in which:

FIG. 1 schematically represents an extracorporeal blood treatmentapparatus made according to an illustrating embodiment;

FIG. 2 is a schematic representing the main steps of the method of thepresent description;

FIG. 3 is a diagram showing dialysis fluid and dialysate conductivityvalues at the start of the treatment when performing a calculationaccording to an embodiment of the invention;

FIG. 4 is a diagram showing dialysis fluid and dialysate conductivityvalues after adjusting sodium concentration in dialysis fluid to run anisotonic dialysis treatment.

DETAILED DESCRIPTION

FIG. 1 illustrates an extracorporeal blood treatment apparatus 1 in anembodiment of the invention.

An example of a hydraulic circuit 100 is schematically illustrated, butit is to be noted that the specific structure of the hydraulic circuit100 is not relevant for the purposes of the present invention andtherefore other and different circuits to those specifically shown inFIG. 1 might be used in consequence of the functional and design needsof each single medical apparatus.

The hydraulic circuit 100 exhibits a dialysis fluid circuit 32presenting at least one dialysis supply line 8, destined to transport adialysis liquid from at least one source 14 towards a treatment station15 where one or more filtration units 2, or dialyzers, operate.

The dialysis fluid circuit 32 further comprises at least one dialysiseffluent line 13, destined for the transport of a dialysate liquid(spent dialysate and liquid ultrafiltered from the blood through asemipermeable membrane 5) from the treatment station 15 towards anevacuation zone, schematically denoted by 16 in FIG. 1 .

The hydraulic circuit cooperates with a blood circuit 17, alsoschematically represented in FIG. 1 in its basic component parts. Thespecific structure of the blood circuit is also not fundamental, withreference to the present invention. Thus, with reference to FIG. 1 , abrief description of a possible embodiment of a blood circuit is made,which is however provided purely by way of non-limiting example.

The blood circuit 17 of FIG. 1 comprises a blood withdrawal line 6designed to remove blood from a vascular access 18 and a blood returnline 7 designed to return the treated blood to the vascular access 18.

The blood circuit 17 of FIG. 1 further comprises a primary chamber 3, orblood chamber, of the blood filtration unit 2, the secondary chamber 4of which is connected to the hydraulic circuit 100.

In greater detail, the blood withdrawal line 6 is connected at the inletof the primary chamber 3, while the blood return line 7 is connected atthe outlet of the primary chamber 3.

In turn, the dialysis supply line 8 is connected at the inlet of thesecondary chamber 4, while the dialysis effluent line 13 is connected atthe outlet of the secondary chamber 4.

The filtration unit 2, for example a dialyzer or a plasma filter or ahemofilter or a hemodiafilter, comprises, as mentioned, the two chambers3 and 4 which are separated by a semipermeable membrane 5, for exampleof the hollow-fibre type or plate type.

The blood circuit 17 may also comprise one or more air separators 19: inthe example of FIG. 1 a separator 19 is included at the blood returnline 7, upstream of a safety valve 20.

Of course other air separators may be present in the blood circuit, suchas positioned along the blood withdrawal line 6.

The safety valve 20 may be activated to close the blood return line 7when, for example, for security reasons the blood return to the vascularaccess 18 has to be halted.

The extracorporeal blood treatment apparatus 1 may also comprise one ormore blood pumps 21, for example positive displacement pumps such asperistaltic pumps; in the example of FIG. 1 , a blood pump 21 isincluded on the blood withdrawal line 6.

The apparatus of above-described embodiment may also comprise a userinterface 22 (e.g. a graphic user interface or GUI) and a control unit12, i.e. a programmed/programmable control unit, connected to the userinterface.

The control unit 12 may, for example, comprise one or more digitalmicroprocessor units or one or more analog units or other combinationsof analog units and digital units. Relating by way of example to amicroprocessor unit, once the unit has performed a special program (forexample a program coming from outside or directly integrated on themicroprocessor card), the unit is programmed, defining a plurality offunctional blocks which constitute means each designed to performrespective operations as better described in the following description.

In combination with one or more of the above characteristics, themedical apparatus may also comprise a closing device operating, forexample, in the blood circuit 17 and/or in the dialysis fluid circuit 32and commandable between one first operating condition, in which theclosing device allows a liquid to flow towards the filtration unit 2,and a second operative position, in which the closing device blocks thepassage of liquid towards the filtration unit 2.

In this case, the control unit 12 may be connected to the closing deviceand programmed to drive the closing device to pass from the first to thesecond operative condition, should an alarm condition have beendetected.

In FIG. 1 the closing device includes the safety valve 20 (e.g. asolenoid valve) controlled by the unit 12 as described above. Obviouslya valve of another nature, either an occlusive pump or a further memberconfigured to selectively prevent and enable fluid passage may be used.

Alternatively or additionally to the safety valve 20, the closing devicemay also comprise a bypass line 23 which connects the dialysis fluidsupply line 8 and the dialysate effluent line 13 bypassing the dialyzer,and one or more fluid check members 24 connected to the control unit 12for selectively opening and closing the bypass line 23. The components(bypass line 23 and fluid check members 24), which may be alternative oradditional to the presence of the safety valve 20 are represented by abroken line in FIG. 1 .

The check members 24 on command of the control unit close the fluidpassage towards the treatment zone and connect the source 14 directlywith the dialysis effluent line 13 through the bypass line 23.

Again with the aim of controlling the fluid passage towards thefiltration unit 2, a dialysis fluid pump 25 and a dialysate pump 26 maybe included, located respectively on the dialysis fluid supply line 8and on the dialysate effluent line 13 and also operatively connected tothe control unit 12.

The apparatus also comprises a dialysis fluid preparation device 9 whichmay be of any known type, for example including one or more concentratesources 27, 28 and respective concentrate pumps 29, 30 for the delivery,as well as at least a conductivity sensor 35.

Of course other kinds of dialysis fluid preparation devices 9 might beequivalently used, having a single or further concentrate sources and/ora single or more pumps.

Since the dialysis apparatus may comprise various liquid sources 14 (forexample one or more water sources, one or more concentrate sources 27,28, one or more sources 33 of disinfectant liquids) connected to thedialysis supply line 8 with respective delivery lines 36, 37 and 38, theapparatus may exhibit, at each delivery line, a respective check member(not all are shown) and, for example, comprising a valve member 31 and34 and/or an occlusive pump.

The preparation device 9 may be any known system configured for on-linepreparing dialysis fluid from water and concentrates.

The dialysis supply line 8 fluidly connects the preparation device 9 forpreparing dialysis fluid to the filtration unit 2. The preparationdevice 9 may be, for example, the one described in the U.S. Pat. No.6,123,847 the content of which is herein incorporated by reference.

As shown, the dialysis supply line 8 connects the preparation device 9for preparing dialysis fluid to the filtration unit 2 and comprises amain line 40 whose upstream end is intended to be connected to a source14 of running water.

Delivery line/s 36/37 is/are connected to this main line 40, the freeend of which delivery line/s is/are intended to be in fluidcommunication (for example immersed) in a container/s 27, 28 for aconcentrated saline solution each containing sodium chloride and/orcalcium chloride and/or magnesium chloride and/or potassium chloride.

Concentrate pump/s 29, 30 is/are arranged in the delivery line/s 36/37in order to allow the metered mixing of water and concentrated solutionin the main line 40. The concentrate pump/s 29, 30 is/are driven on thebasis of the comparison between 1) a target conductivity value for themixture of liquids formed where the main line 40 joins the deliveryline/s 36/37, and 2) the value of the conductivity of this mixturemeasured by means of a conductivity sensor 35 arranged in the main line40 immediately downstream of the junction between the main line 40 andthe delivery line/s 36/37.

Therefore, as mentioned, the dialysis fluid may contain, for example,ions of sodium, calcium, magnesium, and potassium and the preparationdevice 9 may be configured to prepare the dialysis fluid on the basis ofa comparison between a target conductivity value and an actualconductivity value of the dialysis fluid measured by the conductivitysensor 35 of the device 9.

The preparation device 9 comprises regulating means 10, of a known type(i.e. concentrate pump/s 29, 30), which is configured to regulate theconcentration of a specific substance, in particular an ionic substance,in the dialysis liquid. Generally it is advantageous to control thesodium concentration of the dialysis fluid.

The dialysis supply line 8 forms an extension of the main line 40 of thepreparation device 9 for preparing dialysis fluid. Arranged in thisdialysis supply line, in the direction in which the liquid circulates,there are the first flow meter 41 and the dialysis fluid pump 25.

The dialysis effluent line 13 may be provided with a dialysate pump 26and a second flow meter 42. The first and second flow meters 41, 42 maybe used to control (in a known manner) the fluid balance of a patientconnected to the blood circuit 17 during a dialysis session.

A sensor 11 is provided on the dialysis effluent line 13, immediatelydownstream the filtration unit 2, to measure a parameter value of thedialysate in the dialysate effluent line.

In detail, the parameter of the dialysate, which is measured by thesensor 11 is at least one chosen in the group consisting of conductivityof the dialysate, a conductivity-related parameter of the dialysate,concentration of at least a substance in the dialysate and aconcentration-related parameter of at least a substance in thedialysate.

In detail the sensor 11 is a conductivity sensor, which is connected tothe dialysis effluent line 13, and is configured to detect conductivityvalues of the dialysate downstream of the filtration unit 2.

Alternatively (or in combination) sensor 11 may include a concentrationsensor configured for measuring the concentration of at least onesubstance in the dialysate, such as sodium concentration.

Correspondingly, sensor 35 on the dialysis fluid supply line may be nota conductivity sensor and, differently, may include a concentrationsensor configured for measuring the concentration of at least onesubstance in the dialysis fluid, such as sodium concentration.

The control unit 12 of the dialysis apparatus represented in FIG. 1 maybe connected to a (graphic) user interface 22 through which it mayreceive instructions, for example target values, such as blood flow rateQ_(b), dialysis fluid flow rate Q_(di), infusion liquid flow rateQ_(inf) (where appropriate), patient weight loss WL. The control unit 12furthermore may receive detected values by the sensors of the apparatus,such as the aforementioned flow meters 41, 42, the (e.g. conductivity)sensor 35 of the preparation device 9 and the (e.g. conductivity) sensor11 in the dialysis effluent line 13. On the basis of the instructionsreceived and the operating modes and algorithms which have beenprogrammed, the control unit 12 drives the actuators of the apparatus,such as the blood pump 21, the aforementioned dialysis fluid anddialysate pumps 25, 26, and the preparation device 9.

As already mentioned, the described embodiments are intended to benon-limiting examples. In particular the circuits of FIG. 1 should notbe interpreted as defining or limiting, as an apparatus such as in theinvention may comprise other additional or alternative components tothose described.

For example an ultrafiltration line may be included, with at least onerespective pump connected to the dialysis effluent line 13.

One or more infusion lines 39 may also be included, with respectiveinfusion pumps 43 or flow regulation valves, the infusion lines beingconnected up to the blood return line 7 and/or the blood withdrawal line6 and/or directly to the patient. The liquid sources for the infusionlines may be pre-packaged bags 44 and/or liquids prepared by theapparatus itself.

In the example of FIG. 1 , an infusion line 39 is shown directlyconnected to the blood return line 7, in particular to the air separator19. The infusion line 39 may either receive infusion liquid from apre-packaged bag 44 (solid line 45 a) or from an online preparationtrough branch 45 b (dotted line).

Of course a pre-infusion line may be alternatively or additionallyprovided receiving the infusion liquid from a bag or from an onlinepreparation device.

The blood circuit of FIG. 1 is intended for double needle treatments;however, this is a non-limiting example of the blood set.

Indeed, the apparatus may be configured to perform single needletreatments, i.e. the patient is connected to the extracorporeal bloodcircuit by way of a single needle and the extracorporeal line from thepatient is then split into a withdrawal line and a return line, using,for example, an ‘Y’ connector. During single needle treatment, a bloodwithdrawal phase removing blood from patient is alternated to a bloodreturn phase in which blood is restituted to the patient.

Furthermore one or more devices for measuring specific substanceconcentrations might be implemented either (or both) in the dialysisfluid side or (and) in the blood side of the hydraulic circuit.Concentration of calcium, potassium, magnesium, bicarbonate, and/orsodium might be desired to be known.

Finally, the above-cited one or more pumps and all the other necessarytemperature, pressure, and concentration sensors may operate either onthe dialysis supply line 8 and/or on the dialysis effluent line 13, inorder to adequately monitor the preparation and movement of the liquidin the hydraulic circuit.

Given the above description of a possible embodiment of extracorporealblood treatment apparatus, thereafter the specific working of theapparatus and the algorithm programming the control unit are described.

Definitions

We define the “dialysis fluid” as the fluid prepared and introduced tothe second chamber (4) of the filtration unit (2), the dialyzer. Thedialysis fluid may also be denoted “fresh dialysis fluid”.

We define the “dialysate” as the fluid from the outlet from the secondchamber (4) of the filtration unit (2), the dialyzer. Dialysate is thespent dialysis fluid, comprising the uremic toxins removed from theblood.

We define ‘isonatremic dialysis’ as a treatment where the sodiumconcentration of the dialysis fluid does not change pre- topost-filtration unit 2.

We define ‘isotonic dialysis’, as a dialysis where the tonicity of thedialysis fluid does not change pre- to post-filtration unit 2.

We define an ‘isonatrikalemic dialysis’, as a treatment where the sum ofsodium and potassium concentrations of the dialysis fluid does notchange pre- to post-filtration unit 2.

We define ‘isoconductive dialysis’, as a dialysis treatment where theconductivity of the dialysis fluid does not change pre- topost-filtration unit 2, □_(di)=□□_(do).

We define ‘plasma conductivity’ (PC, □_(p)) as the conductivity of thedialysis fluid in an isoconductive dialysis.

In this application, when “isotonic treatment” word is used alone, thisactually implies isotonic, isonatremic or isonatrikalemic dialyses.

In this application the term “citrate” means that the component is inform of a salt of citric acid, such as sodium, magnesium, calcium, orpotassium salt thereof. The citric acid (denoted C₆H₈O₇) is deprotonatedstepwise, therefore the “citrate” include all the different forms,citrate (denoted C₆H₅O₇ ³⁻), hydrogen citrate (denoted C₆H₆O₇ ²⁻), anddihydrogen citrate (denoted C₆H₇O⁷⁻).

The term “citrate” or “total citrate” means the total amount of citricacid and any salts thereof, such as its sodium, magnesium, calcium, orpotassium salt thereof.

In other terms, “total citrate” is the sum of free citrate ions andcitrate containing complexes and ion pairs.

Glossary

The following terms are consistently used throughout the equationsprovided in the following description of the detailed working of theextracorporeal blood treatment apparatus.

Name Description Unit κ_(d,pre) = κ_(di) Dialysis fluid conductivitymS/cm upstream the filtration unit (corresponding to final conductivityof the dialysis fluid); κ_(d,post) = κ_(do) Dialysate conductivity mS/cmdownstream the filtration unit; PC = κ_(p) Plasma conductivity; mS/cmQ_(di) Dialysis fluid flow rate at mL/min filtration unit inlet; Q_(uf)Ultrafiltration flow rate; mL/min Q_(do) Dialysate flow rate atfiltration mL/min unit outlet (i.e., Q_(di) + Q_(uf)); Q_(bset) Setblood flow rate at filtration mL/min unit inlet; Q_(b) Real blood flowrate at filtration mL/min unit inlet (set blood flow compensated forarterial pressure); Q_(bw) Real blood water flow rate mL/min atfiltration unit inlet; K_(u) Filtration unit clearance for urea; mL/minK_(b) _(Cit) bot Filtration unit clearance mL/min for citrate; KoA Ureamass transfer coefficient mL/min of filtration unit (average of normallyused dialyzers); c_(di,Na,start) Dialysis fluid concentration of mmol/Lsodium ions (Na⁺) at the start of treatment, automatically calculatedand set by the machine before the start of the treatment;c_(di,Na,□p,pre) Dialysis fluid concentration mmol/L of sodium ions(Na⁺) at isoconductive dialysis, i.e., when the dialysis fluidconductivity κ_(di) matches the estimated pre-dialysis plasmaconductivity κ_(p,pre); c_(di,Na,set) Dialysis fluid concentration ofmmol/L sodium ions (Na⁺) to provide isotonic or isonatremic orisonatrikalemic dialysis; c_(di,Na,set,isotonic) Dialysis fluidconcentration mmol/L of sodium ions (Na⁺) to provide isotonic dialysis;c_(di,Na,isotonic,adj) Sodium set point adjustment mmol/L (relative toisoconductive state) required to provide isotonic dialysis;c_(di,Na,set,isoNa) Dialysis fluid concentration mmol/L of sodium toprovide isonatremic dialysis; c_(di,Na,isoNa,adj) Sodium set pointadjustment mmol/L (relative to isoconductive state) required to provideisonatremic dialysis; c_(di,Na,set,isoNa+K) Dialysis fluid concentrationmmol/L of sodium to provide isonatrikalemic dialysis;c_(di,Na,isoNa+K,adj) Sodium set point adjustment mmol/L (relative toisoconductive state) required to provide isonatrikalemic dialysis;c_(di,Na,set,) Sodium concentration set point mmol/L _(compensated) tocompensate unintended sodium transfers; c_(di,Na,set,actual) Actualdialysis fluid sodium mmol/L concentration set point during thetreatment at the time an additional compensation is to be applied forc_(di,HCO3) Dialysis fluid concentration mmol/L of bicarbonate as set bythe operator; c_(di,K) Dialysis fluid concentration mmol/L of potassiumions (K⁺) as determined by the used concentrate; c_(di,Ac) Dialysisfluid concentration mmol/L of acetate as determined by the usedconcentrate; c_(di,Na) ₃ _(Cit) Dialysis fluid concentration of mmol/Ltotal citrate as determined by the used concentrate; c_(di,g) Dialysisfluid concentration of mmol/L glucose as determined by the usedconcentrate; c_(pw,Na) Estimated or measured pre-dialysis mmol/Lconcentration of sodium ions (Na⁻) in plasma water; c_(pw,HCO3)Estimated or measured mmol/L pre-dialysis concentration of bicarbonateanions (HCO₃ ⁻) in plasma water; c_(pw,Ac) Estimated or measured mmol/Lpre-dialysis concentration of acetate anions (CH₃COO⁻) in plasma water;c_(pw,K) Estimated or measured mmol/L pre-dialysis concentration ofpotassium ions (K⁺) in plasma water; c_(pw,Na) ₃ _(Cit) Estimated ormeasured or known mmol/L pre-dialysis concentration of total citrate inplasma water c_(p,g) Estimated or measured pre-dialysis mmol/Lconcentration of glucose in plasma; c_(p,u) Estimated or measuredpre-dialysis mmol/L concentration of urea in plasma; f_(bw) Apparentblood water fraction, dimensionless i.e., the part of whole blood thatappears as pure water for urea; f_(pw) Plasma water fraction, i.e., thedimensionless part of plasma that is pure water; f_(g,KB) Glucoseclearance fraction, dimensionless i.e., the relative glucose clearancecompared to urea clearance; □_(0,di) Dialysis fluid conductivity atmS/cm filtration unit inlet for a pure electrolyte solution (i.e.without glucose, either because the actual solution does not containglucose, or because the conductivity has been compensated for theinfluence of glucose); □_(0,do) Dialysate conductivity at filtrationmS/cm unit outlet for a pure electrolyte solution (i.e. without glucoseand urea, because the conductivity has been compensated for theinfluence of glucose and urea); □_(p,1 and) □_(p,2) 1st and 2nd estimateof mS/cm plasma conductivity; □_(p,pre) Estimate of plasma conductivitymS/cm at beginning of treatment (representing a pre-dialysis value);□_(isotonic) Conductivity offset between mS/cm □_(do) and □_(di) toprovide isotonic dialysis (correspondent to c_(di,Na,isotonic,adj));□_(isoNa) Conductivity offset between mS/cm □_(do) and □_(di) to provideisonatremic dialysis (correspondent to C_(di,Na,isoNa,adj)); □_(isoNa+K)Conductivity offset between mS/cm □_(do) and □_(di) to provideisonatrikalemic dialysis (correspondent to c_(di,Na,isoNa+K,adj));□_(rest1) Conductivity contribution mS/cm from lesser solutes 1;□_(rest2) Conductivity contribution mS/cm from lesser solutes 2;□_(rest3) Conductivity contribution mS/cm from lesser solutes 3; □_(g)Conductivity correction M − 1 = L/mol term for glucose; □_(u)Conductivity correction M − 1 = L/mol term for urea; M _(κ) _(NaHCO3)Molar conductivity of sodium L · mS/mol · cm bicarbonate (NaHCO₃) ationic strength 150 mM; M _(κ) _(NaCl) Molar conductivity of sodium L ·mS/mol · cm chloride (NaCl) at ionic strength 150 mM; M _(κ) _(NaAc)Molar conductivity of sodium L · mS/mol · cm acetate (NaCH₃COO) at ionicstrength 150 mM; M _(κ) _(KCl) Molar conductivity of potassium L ·mS/mol · cm chloride (KCl) at ionic strength 150 mM; M _(Na) ₃ _(Cit)Molar conductivity of trisodium L · mS/mol · cm citrate (Na₃C₆H₅O₇) ationic strength 150 mM; T Set total treatment time; min T Elapsed timeinto treatment; min A Donnan factor

The Donnan factor indicates a value of electroneutrality to be kept overthe membrane. For estimating the Donnan factor reference is made toTrans Am Soc Artif Intern Organs, 1983; 29; 684-7, “Sodium Fluxes duringhemodialysis”, Lauer A., Belledonne M., Saccaggi A., Glabman S., BoschJ.

Solution Proposal

The technical solution here described consists of three main parts:

-   -   Estimating PC at the beginning of the treatment (i.e.,        □_(p,pre));    -   Setting the dialysis fluid sodium concentration such that the        dialysis fluid tonicity (or sodium or sodium+potassium) is not        changed during its passage through the filtration unit;    -   Maintaining the dialysis fluid composition throughout the whole        treatment.

The various steps of the proposed method described below are intended tobe performed by the control unit 12 of the extracorporeal bloodtreatment device 1, even if not explicitly stated.

In particular a treatment session is started, preferably, but notnecessarily, as a double needle hemodialysis treatment.

The user shall input the prescription values through the user interface22. For example the set values for total weight loss WL and totaltreatment time T are provided, as well as the blood flow rate Q_(b) andthe fresh dialysis flow rate Q_(di).

Other parameters may be entered through the user interface, such as bagtype, sodium user limits, etc.

The operator has to further input the ‘bicarbonate’ set before startingthe treatment.

The control unit 12 calculates either the initial dialysis liquidconductivity or the initial concentration of at least one solute, e.g.sodium, in the dialysis liquid in order to start with a dialysis fluidconductivity as close as possible to the expected patient pre-dialyticplasma conductivity.

In order to not disturb the tonicity of the patient, it is necessary toset the fluid composition as quickly as possible so that the patientinitial plasma conductivity is not inadvertently changed. Thus,estimating of the plasma conductivity has to be done as rapidly aspossible when treatment starts; moreover, since the estimation ispreferably performed only once, this measure should be as reliable aspossible.

In this respect it is worth to note that, in the following detaileddescription, reference is made to regulating means controllingconcentration of an ionic substance, in detail sodium concentration, inthe preparation of the dialysis fluid so as to obtain a desiredconductivity of the dialysis fluid.

However, regulating means directly regulating the overall dialysis fluidconductivity is also included in the spirit of the present descriptionor, alternatively, regulating means modifying the concentration of adifferent ionic substance is included in the present description, too.

Given the above, the control unit 12 sets a parameter value for thedialysis fluid in the dialysis fluid supply line 8 at an initial setpoint; in general the parameter of the dialysis fluid is either theconductivity of the dialysis fluid, or a conductivity-related parameterof the dialysis fluid, or concentration of at least a substance (inparticular an ionic substance and in more detail sodium) in the dialysisfluid, or a concentration-related parameter of at least a substance(e.g. sodium) in the dialysis fluid.

In detail, the control unit 12 is configured to set the parameter valuefor the dialysis fluid at the initial set point so that a dialysis fluidconductivity matches a first estimate of the plasma conductivity of theblood.

In the specific, the control unit 12 calculates the initial set point ofthe substance concentration and drives the regulating means 10 acting onthe sodium concentration in the dialysis liquid.

The set point is calculated before starting the blood circulation (i.e.before starting the treatment).

In order to calculate the dialysis composition initial set pointalternative ways might be used, e.g. determine a certain sodiumconcentration (see below), or using an average plasma conductivity froma large population, or using an average plasma conductivity from a largepopulation corrected for the composition of the dialysis fluid, orcalculate based on historic patient data.

In any case, the initial set point for the dialysis liquid is calculatedby the control unit 12 so that the expected plasma conductivity is thebest guess of plasma conductivity that may be calculated, without priorknowledge of the individual patient.

In general terms, the control unit is configured to calculate theinitial set point of the substance concentration to be set (e.g. sodium)in the dialysis fluid as a function of the difference in concentrationof at least one (and in detail several) further substance in thedialysis fluid and the same further substance in the plasma.

The calculation is based on average pre-dialysis concentrations of atleast one (and preferably all) substance chosen between sodium,potassium, acetate, citrate, and bicarbonate (as well as other solutes)in a large patient population, plus the contribution related to dialysisfluid of bicarbonate, potassium, acetate, and citrate resulting from theprescription and from the chosen concentrate combination.

The control unit 12 calculates the initial set point also as a functionof the concentration of at least one, in particular two, and preciselyall the substances in the dialysis fluid included in the groupcomprising bicarbonate, potassium, acetate, and citrate.

Furthermore, the control unit 12 calculates the initial set point of thesubstance (i.e. sodium) in the dialysis fluid also as a function of thedifference in concentration of one or more further substances in thedialysis fluid different from sodium; in particular these substancesinclude bicarbonate, potassium, acetate, and citrate and two, andprecisely all, the differences, in particular weighted differences, inconcentration value of the mentioned substances in the dialysis fluidand in the plasma are taken into account.

The control unit 12 calculates the initial set point of the substance inthe dialysis fluid also as a function of the molar conductivities of oneor more substances, such as one, two, three, or all of the followingsubstances in the dialysis fluid which are sodium bicarbonate (NaHCO₃),sodium chloride (NaCl), sodium acetate (NaCH₃COO), trisodium citrate(Na₃C₆H₅O₇), potassium chloride (KCl), and sodium lactate (Na₃C₃H₅O₃).

The control unit 12 calculates the initial set point of the substance inthe dialysis fluid as a function of an estimated plasma waterconcentration of at least sodium, and/or bicarbonate, and/or potassiumand/or acetate and/or citrate. The estimated plasma water concentrationof sodium, bicarbonate, potassium, acetate, and citrate, is, forexample, the mean pre-dialysis values of the corresponding substance forlarge patient populations, or historical document for a particularpatient.

The initial set point may also be a function of one or more flow rates,in particular of the dialysate flow rate at the outlet of the secondarychamber 4.

Also an efficiency parameter of the filtration unit 2 plays a role inthe initial set point calculation of sodium. In particular a clearanceof the filtration unit 2 may be used (e.g. the urea clearance).

Specifically, the control unit 12 is configured to calculate the initialset point of sodium concentration to be set in the dialysis fluid beforethe start of the treatment using the following relationship:

$\begin{matrix}{c_{{di},{Na},{start}} = {{\alpha*c_{{pw},{Na}}} + {\frac{1}{M_{\kappa_{NaCl}}}\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)++}\frac{1}{M_{\kappa_{NaCl}}}\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)} + {\frac{M_{\kappa_{KCl}}}{M_{\kappa_{NaCl}}}{\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)++}\frac{1}{M_{\kappa_{NaCl}}}\frac{Q_{do}}{K_{u}}\kappa_{{rest}3}}}} & (1)\end{matrix}$

wherein the used symbols meaning is clarified in the glossary section.

In case also citrate has to be taken into consideration, the controlunit 12 may alternatively use the following relationship:

$\begin{matrix}{c_{{di},{Na},{start}} = {{\alpha*c_{{pw},{Na}}} + {\frac{1}{M_{\kappa_{NaCl}}}\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)++}\frac{1}{M_{\kappa_{NaCl}}}\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)} + {\frac{M_{\kappa_{KCl}}}{M_{\kappa_{NaCl}}}{\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)++}\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{{Na}_{3}{Cit}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\alpha^{- 3}} + {0.125\alpha^{- 2}} + {0.706\alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{{di},{{Na}_{3}{Cit}}}} \right)++}\frac{1}{M_{\kappa_{NaCl}}}\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}}} & \left( {1a} \right)\end{matrix}$

wherein the used symbols meaning is clarified in the glossary section.

Since K_(u) may not be known at dialysis start, a fixed value equal toQ_(di)/2 may be possibly used, or of formula (6) below with K_(o)A asmean value of used type of filtration unit or the value for the actualfiltration unit. K_(b) _(Cit) is the approximated clearance value forcitrate (for calculation/estimation see below description).

Of course, different mathematical relationships may be used taking intoaccount exclusively some of the considered substances and/or exclusivelysome of the conductivities and/or molar differences.

Once the sodium initial set point has been calculated and acorresponding dialysis fluid has been prepared by the control unit 12driving the regulating means 10, the treatment may start.

The dialysis fluid is circulated through the dialysis fluid circuit 32and the secondary chamber 4 of the filtration unit 2 so as to exchangewith blood.

Correspondingly, blood is withdrawn from the patient and circulated inthe extracorporeal blood circuit 17 and particularly is circulatedthrough the primary chamber 3 of the filtration unit 2.

At least one, and in general a plurality, of consecutive initial valuesof the parameter (in the specific example, the conductivity) of thedialysate downstream of the secondary chamber 4 are measured at thebeginning of the treatment through sensor 11.

The control unit 12 is configured to validate and further process themeasurement of an initial value of the conductivity of the dialysate assoon as the diffusion process in the filtration unit 2 reaches stableconditions.

Indeed, a transient exists when dialysis fluid and blood startexchanging during which the dialyzer outlet conductivity is not stable;during the transient period the measured outlet conductivity valuesshould be disregarded.

Stable conditions for the diffusion process may be determined in caseone or more of the following conditions occurs:

-   -   a first derivative of the median or of the average value of the        conductivity of the dialysate is lower in size than a first        threshold;    -   a first derivative of the value of conductivity of the dialysate        is lower in size than a first threshold for a specified time        window;    -   a first derivative of the filtered value of conductivity of the        dialysate is lower in size than a first threshold for a        specified time window, the filtered value being a value filtered        either by a median filter (which picks out the median) or a        linear filter, either a finite impulse response filter (which is        equal to a weighted average), or an infinite impulse response        filter (which is standard, but has the form yf(t)=−a1*yf(t−1)− .        . . −an*yf(t−n)+b1*y(t−k−1)+ . . . +bm*y(t−k−m), where yf(t) is        the filtered value at time t, y(t) is the measured value at time        t, n and m are the number of parameters a and b (the order) of        the filter and k is the number of pure time delays);    -   a second derivative of the median value of the conductivity of        the dialysate is lower in size than a second threshold;    -   a second derivative of the filtered value of conductivity of the        dialysate is lower in size than a first threshold for a        specified time window;    -   a change or a relative change of the value itself or a filtered        version of the value of the conductivity since a fixed previous        point in time is below a first threshold (an expanding window);    -   a change or the relative change of the value itself or a        filtered version of the value of the conductivity since a fixed        time interval backwards is below a first threshold (a sliding        window, constant in length);    -   a prefixed time has lapsed after starting circulation of both        blood and fresh dialysis fluid in the filtration unit, in        particular said pre-fixed time being not more than 15 minutes;    -   a variable time has lapsed after starting circulation of both        blood and dialysis fluid in the filtration unit, said variable        time being function of at least one parameter, such as the        volume of the secondary chamber 4 of the filtration unit 2; in        particular the variable time may be a function of further        parameters such as dialysis fluid flow rate, blood flow rate,        filtration unit permeability, etc.

The stability condition is preferably determined by observing, on a1-minute window, the first derivative of □_(do) and checking when it islower in size than a fixed threshold. Once this stability criterion isfulfilled, □_(do) is taken as the median value on the 1-minute window.The first derivative is used to avoid the presence of possible drifts inthe outlet conductivity. Extracting the median and/or the average valueof □_(do) allows discharging possible outliers of the outletconductivity signal from the average calculation.

In order to minimize the time needed to reach stability conditions,changes in dialysis fluid flow rate and in bicarbonate prescription maybe prevented during this preliminary isotonic sodium identificationphase.

Changes in blood flow, ultrafiltration flow rate or bypass are viceversa generally allowed, but they will delay stability. Moreover, it isnot possible to change the concentrate combination type after thetreatment is started.

Alternatively, it might be possible to just estimate the initial valueof the conductivity of the dialysate fluid representative of theconditions prevailing after the diffusion process has reached stableconditions; the estimate is based on one or more conductivitymeasurements in the dialysate before reaching the stable conditions andusing proper estimate algorithms.

Glucose and urea, the main electrically neutral substances in dialysisfluid, reduce the conductivity of the dialysis fluid. The effect issmall but noticeable and leads to a plasma conductivity underestimationand thus to an underestimation of the plasma sodium. Hence, acompensation for urea and glucose contribution may also be applied tothe measured conductivities □_(di) and ≡_(do): the resultingconductivities for pure ion solutions (□_(0,di) and □_(0,do)) mayalternatively be used in all the calculations using conductivitiesreported below.

The control unit 12 may compensate the measured initial conductivityvalue of the dialysate as a function of the concentration of at leastglucose.

Moreover, the control unit may compensate the measured initialconductivity value of the dialysate as a function of a flow rate, suchas the dialysate flow rate at the outlet.

The control unit 12 may compensate the measured initial conductivityvalue of the dialysate as a function of an efficiency parameter of thefiltration unit 2, (e.g. a clearance of the filtration unit 2, in detailthe urea clearance).

Furthermore, the control unit 12 may compensate the measured initialconductivity value of the dialysate as a function of an estimated plasmaconcentration of glucose and/or urea.

The specific formula to compensate the measured initial conductivityvalue of the dialysate is the following:

$\begin{matrix}{\kappa_{0,{do}} = \frac{\kappa_{do}}{\left( {1 - {{\gamma_{g}\left( {c_{{di},g} + {\frac{f_{g,K_{B}}K_{u}}{Q_{do}}\left( {\frac{c_{p,g}}{f_{pw}} - c_{{di},g}} \right)}} \right)}\left( {1 - {\gamma_{u}\frac{K_{u}}{Q_{do}}\frac{c_{p,u}}{f_{pw}}}} \right)}} \right.}} & (2)\end{matrix}$

The significance of the denotations and constants above is given in theGlossary.

The control unit 12 may be configured to compensate the initialconductivity of the dialysis fluid as a function of the concentration ofglucose, if glucose is present in the dialysis liquid.

The control unit 12 is specifically configured to compensate the initialconductivity of the fresh dialysis fluid using the following formula:

$\begin{matrix}{\kappa_{0,{di}} = \frac{\kappa_{di}}{1 - {\gamma_{g}c_{{di},g}}}} & (3)\end{matrix}$

The significance of the denotations and constants above is given in theGlossary.

It is worth to note that the initial conductivity of the fresh dialysisfluid upstream the secondary chamber 4 may be either measured or takenas the set value for dialysis conductivity.

In general, it is preferred to measure the initial conductivity of thedialysis fluid through the sensor 35, too.

It is important to underline that the initial setting of the sodiumconcentration calculated or determined as above stated to be as close aspossible to the expected plasma conductivity (eq. 1) may be optional,meaning that the method for estimating the initial plasma conductivitymay be performed even if the sodium content of the dialysis conductivityis initially simply set by the operator.

Also correction based on main electrically neutral substances isoptional and may be used or not to increase accuracy.

The compensation for the main electrically neutral substances (e.g. ureaand glucose) may be alternatively applied to the final adjustmentcontribution terms.

Vice versa, it is relevant to measure at least the conductivitydownstream the filtration unit (and preferably also the conductivityupstream the filtration unit) as soon as possible, i.e. as soon asstable conditions are reached or as soon as an estimate of suchconductivity in stable conditions may be performed.

This is due to the need of matching as much as possible the patientinitial plasma conductivity which is clearly affected/changed by thedifferent conductivity of the dialysis fluid circulating during thetreatment.

In order to make a first estimate of the plasma conductivity based onmeasured values, two embodiments are provided, which may be usedtogether or alternatively.

Firstly, the control unit 12 calculates the value of the initial plasmaconductivity, based on the measured initial parameter value of thedialysate (i.e. based on conductivity or concentration measurement ofdialysate on the filtration unit outlet) and on the correspondingparameter value of the dialysis fluid in the dialysis fluid supply line8 e.g. conductivity or concentration). During the start of the treatmentand particularly during circulating the dialysis fluid through thesecondary chamber 4 up to measuring the initial value of the parameterof the dialysate downstream of the secondary chamber used for thecalculating of the initial plasma conductivity, the dialysis fluidconductivity (or concentration) is kept substantially constant.

In other words, the calculation of the initial plasma conductivity isperformed with no conductivity step as it was normally made in the priorart devices.

Indeed, both the two embodiments allowing plasma conductivity estimationdo not require to change the dialysis conductivity or the sodium contentin the dialysis liquid and to take measures at the inlet and at theoutlet of the dialyzer in both conditions.

In this respect the term ‘substantially constant’ means that theconductivity of the dialysis fluid is not changed by the machine or bythe operator, but it may not be exactly constant due to smalloscillations on the measured value caused by noise, tolerances in theconcentrate dosing system or tolerances in the conductivitymeasurements. Generally these small variations around the set value areless than 0.2 mS/cm.

Just a single reliable measurement at the inlet and at the outlet of thedialyzer may be sufficient to have a preliminary (to be made moreaccurate) or an already final estimation of the PC.

From a general point of view, the control unit 12 is further configuredto calculate the plasma conductivity as a function of at least one ormore flow rates.

The flow rates include the dialysate flow rate at the outlet of thesecondary chamber 4; in addition, the flow rates may include the bloodflow rate in the blood lines too.

Also an efficiency parameter of the filtration unit 2, in particular aclearance of the filtration unit 2 (e.g. the urea clearance) is used forplasma conductivity. Of course, a nominal clearance and/or a calculatedclearance may be used; the calculated clearance may be both an estimatedclearance as well as a compensated clearance.

Moreover, the plasma conductivity depends on an (possibly compensated)initial conductivity of the dialysate and on a (possibly compensated)conductivity of the dialysis fluid in the dialysis supply line 8.

According to a first embodiment, the control unit 12 is programmed tocalculate the initial plasma conductivity based on the sum of at leastthe initial conductivity of the dialysate plus a difference betweeninlet and outlet conductivity at the filtration unit, or dialyzer,weighted by a factor of the dialysate flow rate. In more detail thedifference between inlet and outlet conductivity at the dialyzer isweighted by a factor of the blood flow rate in the blood lines too.

Specifically, according to the first embodiment, the control unit 12 isconfigured to calculate the plasma conductivity using the followingformula:

$\begin{matrix}{\kappa_{p,1}^{\prime} = {\kappa_{0,{do}} + {\frac{Q_{do}}{Q_{Bset}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}} & (4)\end{matrix}$

The significance of the denotations above is given in the Glossary.

It is worth to underline that during the above described calculation ofthe initial plasma conductivity (formula (4)), the dialysis fluidcirculates through the secondary chamber 4 maintaining the dialysisfluid parameter value substantially constant.

In the second embodiment, the control unit 12 is programmed to calculatethe initial plasma conductivity based on the sum of at least the initialconductivity of the fresh dialysis fluid plus a difference between inletand outlet conductivity at the dialyzer weighted by a factor of thedialysate flow rate. In more detail the difference between inlet andoutlet conductivity at the filtration unit, or dialyzer, is weighted bya factor of the dialyzer clearance too.

Specifically, according to the second embodiment, the control unit 12 isconfigured to calculate the plasma conductivity using the followingformula:

$\begin{matrix}{\kappa_{p,1}^{''} = {\kappa_{0,{di}} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}} & (5)\end{matrix}$

The significance of the denotations and constants above is given in theGlossary.

It is worth to underline that during the above described calculation ofthe initial plasma conductivity (formula (5)), the dialysis fluidcirculates through the secondary chamber 4 maintaining the dialysisfluid parameter value substantially constant.

In more detail, in the formulas above:

-   -   k_(0,di) is the set/measured-by-sensor 35 value for conductivity        of the dialysis fluid, corrected for glucose (see previous        equation);    -   k_(0,do) is the mean value of outlet conductivity on the        stability 1-minute window, corrected for glucose and urea;    -   Q_(di) is the set value for dialysis fluid flow rate;    -   Q_(bset) and Q_(do) are the mean values, respectively, of blood        flow rate set and of dialysate flow rate at the filtration unit,        or dialyzer, outlet, on the stability window;    -   K_(u) is the dialyzer diffusive clearance for urea. Since K_(u)        may not be known at this time, different estimates may be used.

K_(u) may be approximated as Q_(di)/2.

Alternatively, K_(u) may be calculated as follows:

$\begin{matrix}{K_{u} = {{Q_{bw}Q_{di}} = \frac{1 - e^{{KoA}{({\frac{1}{Q_{di}} - \frac{1}{Q_{bw}}})}}}{Q_{di} - {Q_{bw}e^{{KoA}{({\frac{1}{Q_{di}} - \frac{1}{Q_{bw}}})}}}}}} & (6)\end{matrix}$

where

-   -   KoA is either a known value if the control unit has information        about the dialyzer used. In case the control unit has no        information on the used dialyzer, a standard dialyzer value with        a KoA=1100 ml/min as a fixed value is used.    -   Q_(bw) is the blood water flow, for example, calculated as:        Q _(bw) =f _(bw) ·Q _(b)=0.89·Q _(b)  (7)

where Q_(b) is real blood flow rate and f_(bw) is the apparent bloodwater fraction for urea, where a hematocrit of 30% has been assumed.

According to first estimate, k_(p,1) may be found after approx. 6 to 10minutes after treatment start.

Of course, both formulas (4) and (5) for estimation of plasmaconductivity may be iteratively applied, meaning that the newlycalculated estimate of PC (k_(p,1)) is imposed to the dialysis fluid anda new estimate again calculated after taking measures of theconductivity at the inlet and outlet of the filter as soon as stableconditions are reached.

Of course, in case of iteration of anyone of the above calculationsaccording to formulas (4) or (5), after the first plasma conductivityestimation, the dialysis fluid parameter value is changed since thenewly calculated estimate of PC (k_(p,1)) is imposed to the dialysisfluid, meaning that the conductivity of the dialysis fluid is changed.This however does not impact on the fact that the first calculationaccording to formulas (4) and (5) is made without a change in theconductivity of the dialysis fluid.

In one way of exploiting the method, the first formula (4) or the secondformula (5) is applied only once and the estimated PC (k_(p,1)) isconsidered already a good estimation of initial plasma conductivity.

In another way, the first formula (4) is applied twice.

In a further way, the second formula (5) is applied twice; in this case,the dialysis fluid sodium concentration correspondent to k_(p,1)″ isiteratively calculated and applied. k_(d0) is measured again as soon asstable conditions are reached: the stability criteria are the same aspreviously described. A second estimation of PC (k_(p,2)) according toformula (5) is done and k_(p,2) is used as k_(p,pre).

In this second case k_(p,2) should be found after approx. 11-17 minutesafter treatment start.

A further way, the second formula (5) is applied twice.

The above mentioned steps according to one of the described embodimentare schematically shown in FIG. 3 .

It is relevant to note that in equations (4) and (5), k_(do) and k_(di)may be used instead of k_(0,do) and k_(0,di).

A timeout may be provided for each of k_(p,1) and k_(p,2) estimationphases (due to e.g. a change in some parameters). At the end of eitherone of these timeouts (e.g., if the stability has not been reached), analarm shall be triggered to de-activate the isotonic treatmentprocedure. In general it does not make sense to apply isotonic dialysistoo late into the treatment.

The dialysis fluid sodium concentration correspondent to k_(p,pre) isthen determined.

The resulting dialysis fluid sodium concentration applied,c_(di,Na,kp,pre), would correspond to implement an isoconductivedialysis.

However, since an isotonic or isonatremic or isonatrikalemic dialysis isto be applied, this sodium value may be adjusted with a properadjustment factor (depending on the choice to apply isotonic,isonatremic or isonatrikalemic dialysis).

In respect to the above mentioned treatments, it is relevant to note thefollowing.

An isonatremic dialysis may in general terms be considered as atreatment where the sodium concentration in the extracellular fluid ofthe patient is maintained stable or undergoes reduced variationsthroughout treatment.

It is however worth noting that tonicity is determined by the particlesthat are osmotically active.

Actually, the dialysis fluid (and the plasma) contains a multitude ofsubstances that influence tonicity/osmolality, not just sodium, even ifthis is the main determinant of serum osmolality.

Hence, an isotonic dialysis may be considered as a dialysis where thetonicity of the fluids in the patient is maintained stable or undergoesreduced variations throughout dialysis treatment. This would be achievedby maintaining the tonicity of the dialysis fluid substantially equal tothe tonicity of the extracellular fluid throughout treatment. In thiscase, the tonicity of the dialysis fluid does not change pre- topost-filtration unit 2.

An isonatrikalemic dialysis, may in general terms be considered as atreatment where the sum of sodium and potassium concentrations in thepatient extracellular fluid is maintained stable or undergoes reducedvariations throughout dialysis treatment (in this case, the sum ofsodium and potassium concentrations of the dialysis fluid does notchange pre- to post-filtration unit 2).

Considering that a patient shall lose a certain amount of potassiumduring treatment, the isonatrikalemic condition may be maintained with aproportional increase in serum sodium concentration.

An isoconductive dialysis may in general terms be considered as adialysis treatment maintaining the conductivity of the dialysis fluidequal to the conductivity of the extracellular fluid, which in this caseis represented by the plasma conductivity.

The plasma conductivity (PC, □_(p)) is the conductivity at which thedialysis fluid conductivity is not changed during its passage throughthe dialyzer. Then the conductivities upstream and downstream thefiltration unit 2 are equal: □_(di)=□□_(do).

In case of an isotonic or isonatremic or isonatrikalemic treatment is tobe performed, the mentioned adjustment factor is calculated based onmolar conductivities, dialysis fluid composition, and the best estimateof plasma water composition as will better emerge from the followingdescription. The best estimate of plasma water composition may bederived from literature, or may be based on statistical prepared values,or test of patient, or obtained with direct lab measurements made beforethe treatment.

According to an innovative aspect, the control unit 12 receives a valuerepresentative of a parameter of the blood in said blood lines 6, 7. Theblood parameter may be the plasma conductivity or a plasmaconductivity-related parameter.

In particular, the control unit 12 may be programmed for calculating theplasma conductivity, for example executing the method previouslydisclosed or, alternatively using known methods such as those describedin EP 2377563.

Alternatively, the control unit 12 directly receives as an input theplasma conductivity. For example, the physician or the nurse may receivea lab analysis and may provide the datum to the machine through the userinterface of the dialysis monitor; the control unit 12 is programmed forstoring in a memory the plasma conductivity to be used for the followingdialysis fluid parameter regulation.

Finally, the plasma conductivity may be directly measured in vivo by themonitor before starting the treatment session using a proper plasmaconductivity sensor.

The control unit 12 is generally configured for setting a parametervalue for the dialysis fluid in the dialysis supply line 8 at a setpoint.

The parameter of the dialysis fluid is chosen between a conductivity ofthe dialysis fluid, a conductivity-related parameter of the dialysisfluid, a concentration of a substance in the dialysis fluid and aconcentration-related parameter of a substance in the dialysis fluid.

Depending on the specific dialysis monitor, the sodium content (or thecontent of more than one electrolyte) may be regulated in the dialysisline. Alternatively, the control parameter may be the overallconductivity of the dialysis fluid.

The setting of the parameter value in the dialysis fluid (which ishereinafter identified as sodium concentration set point in the dialysisfluid with no limiting effect) includes the sub-step of calculating thesodium concentration set point (at least) as a function of a maincontribution term based on/function of the plasma conductivity and as afunction of an adjustment contribution term, i.e. a term which takesinto account the transport driving gradient of certain specificsubstances. Additionally, compensation for unintended sodium transfermay be applied as explained in detail in the last paragraphs of thepresent description.

The main contribution term may affect (may contribute to) the dialysisfluid sodium concentration set point for at least 80% of the sameparameter value (and in particular for at least 90% of the parametervalue), i.e. the general value of the sodium concentration mainly dependon plasma conductivity.

In more detail, the adjustment contribution term may contribute to thedialysis fluid sodium concentration set point for less than 15% of thesame parameter value (and in particular for less than 10% of theparameter value).

The calculation is an algebraic sum of at least the main contributionterm (c_(di,Na,κ) _(p,pre) ) and the adjustment contribution term(c_(di,Na,adj)) according to the following general formula:c _(di,Na,set) =c _(di,Na,κ) _(p,pre) +c _(di,Na,adj.)

In order to obtain a dialysis fluid sodium implementing a certain kindof dialysis, i.e. C_(di,Na,set), an adjustment factor C_(di,Na,adj)needs to be applied to make the dialysis fluid matching a certainspecific concentration of the plasma.

(c_(di,Na,κ) _(p,pre) ) is the dialysis fluid concentration of sodium atisoconductive state, i.e. when the dialysis fluid conductivity □_(di)matches the estimated pre-dialysis plasma conductivity □_(p,pre).

Though not essential since a calculation may be made based onconductivities too, the main contribution term and the adjustmentcontribution term are dimensionally concentrations of a substance (e.g.sodium) in a fluid.

The adjustment contribution term is the sodium concentration set pointadjustment relative to an isoconductive state to provide a specifictreatment which may be, for example, chosen in the group includingisotonic dialysis, isonatremic dialysis, and isonatrikalemic dialysis.

The Applicant has understood that certain specific substances, namelybicarbonate, potassium, acetate, and citrate have a major effect whichshould be taken into account when it is desired to run an isotonic, orisonatric, or isonatrikalemic dialysis treatment. Indeed, anisoconductive dialysis (i.e. a dialysis maintaining the conductivity ofthe dialysis fluid equal to the conductivity of the extracellular fluid,which in this case is represented by the plasma conductivity—as defined,plasma conductivity (PC, □_(p)) as the conductivity at which thedialysis fluid conductivity is not changed during its passage throughthe dialyzer so that the pre-dialyzer and the post-dialyzerconductivities are equal: □_(di)=□_(do)) causes an overload of sodium inthe patient.

To avoid overloading at least the effect of the above substances must betaken into duly consideration. Of course other substances play a role,such as lactate, magnesium, and calcium.

Furthermore, the difference in concentration between same substances inthe blood and in the dialysis fluid influences, as well, the sodiumoverload in case of isoconductive treatments.

Given the above, the Applicant also realized that in calculating theadjustment contribution term, certain parameters having a weight indetermining the overload of sodium are known and depends on the machinedressing (e.g. used concentrates) or on the prescription for the patient(e.g. dialysate flow rate). Other parameters depend on the patientundergoing the treatment and therefore may be either directly measured(e.g. lab analysis) or estimated (e.g. based on large population numbersor patient history).

Since isoconductive dialysis causes sodium overload, the adjustmentcontribution term generally assumes a negative value, i.e. reduces theset point concentration of sodium in the dialysis fluid calculated forisoconductive treatment.

In more detail, the control unit is configured to calculate theadjustment contribution term based on a concentration of at least asubstance in the dialysis fluid chosen in the group includingbicarbonate, potassium, acetate, lactate, and citrate; in particularcalculation is made as a function of the concentration of at least twoof said substances, and in further detail as a function of theconcentration of bicarbonate, potassium, acetate, and/or citrate, andlactate in the dialysis fluid.

As mentioned, the control unit is configured to calculate the adjustmentcontribution term as a function of the difference, in particularweighted difference, in concentration of at least one of the above citedsubstances in the dialysis fluid and the same substances in the bloodplasma.

Additionally, the control unit calculates the adjustment contributionterm as a function of the molar conductivities of at least a substancein the dialysis fluid; in detail the substance may be chosen from thegroup including acids or salts of bicarbonate, chloride, acetate,phosphate, and sulphate, wherein the salt is formed with sodium,potassium, calcium, or magnesium.

In more detail, the calculations take into account the molarconductivities of at least two of said substances, specifically of atleast three and particularly of sodium bicarbonate (NaHCO₃), sodiumchloride (NaCl), sodium acetate (NaCH₃COO), trisodium citrate(Na₃C₆H₅O₇), and potassium chloride (KCl).

Again, the adjustment contribution term is a function of the differencesbetween two molar conductivities, a first molar conductivity of asubstance chosen in the group including sodium bicarbonate (NaHCO₃),sodium acetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), and potassiumchloride (KCl), and a molar conductivity of sodium chloride (NaCl).

Alternatively, the adjustment contribution term is a function of thedifferences between two molar conductivities, a first molar conductivityof a substance chosen in the group including sodium bicarbonate(NaHCO₃), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl),and a molar conductivity of sodium chloride (NaCl).

The control unit is also configured to calculate the adjustmentcontribution term as a function of an estimated plasma waterconcentration of at least a substance chosen in the group includingbicarbonate, potassium, acetate, lactate, and citrate; in particular thecalculation is made based on the estimated plasma water concentration ofat least two, three or four of said substances; in the specific exampleof the present description the adjustment contribution term is afunction of the estimated plasma water concentration of bicarbonate,potassium, and acetate or is a function of the estimated plasma waterconcentration of bicarbonate, potassium, citrate, and acetate.

The estimated plasma water concentration of bicarbonate, potassium,citrate, and acetate is the mean pre-dialysis values of thecorresponding substance for large patient populations. As previouslymentioned, the estimated plasma water concentration of bicarbonate,potassium, and acetate may alternatively be based on other statisticalprepared values, or historical values for the specific patient, ordirect measurements made before the treatment.

Note that, in the specific formula, the estimated plasma waterconcentration is adjusted by a respective (preferably fixed) adjustingfactor. Numerical values can be, e.g. 0.95 or 1.05, but other values maybe used (generally depending on the protein content, or charge of ions).

The adjustment contribution term is an algebraic sum of a plurality ofcomponents, a first component being function of the difference, inparticular weighted difference, in concentration of at least a substancein the dialysis fluid and the same substance in the blood plasma, thesecond component being function of the difference, in particularweighted difference, in concentration of at least a second substance inthe dialysis fluid and the same second substance in the blood plasma,the third component being function of the difference, in particularweighted difference, in concentration of at least a third substance inthe dialysis fluid and the same third substance in the blood plasma,optionally the fourth component being function of the difference, inparticular a weighted difference, in concentration of at least a fourthsubstance in the dialysis fluid and the same fourth substance in theblood plasma, the fifth component depends on at least a ratio betweenone flow rate, in particular the dialysate flow rate at the outlet ofthe secondary chamber 4, and an efficiency parameter of the filtrationunit 2, in particular a clearance of the filtration unit 2, optionallythe urea clearance.

The substance may be chosen in the group including bicarbonate anions(HCO₃ ⁻), acetate anions (CH₃COO⁻), citrate, and potassium ions (K⁺),but additionally also lactate.

The above general consideration is reflected in specific and nonlimiting implementing formulas which allow, when the plasma conductivityis known, to determine the precise set point for sodium concentration inthe dialysis fluid for running an isotonic, isonatremic orisonatrikalemic treatment.

Of course, different formulas including one or more of the generalprinciples/substances above stated may be alternatively used.

In order to obtain a dialysis fluid sodium implementing isotonicdialysis, i.e. c_(di,Na,set,isotonic), an adjustment factorc_(di,Na,isotonic,adj) needs to be applied to make the dialysis fluidmatching the tonicity of the plasma:c _(di,Na,set,isotonic) =c _(di,Na,κ) _(p,pre) +c_(di,Na,isotonic,adj)   (8)

where:

$\begin{matrix}{c_{{di},{Na},{isotonic},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right)\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{{rest}\; 1} + \kappa_{{rest}\; 2}} \right)}} \right)}} & (9)\end{matrix}$

or where the adjustment factor also takes care of citrate according tothe following relationship:

$\begin{matrix}{c_{{di},{Na},{isotonic},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right){\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)++}\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{{Na}_{3}{Cit}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\alpha^{- 3}} + {0.125\alpha^{- 2}} + {0.706\alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{{di},{{Na}_{3}{Cit}}}} \right)++}\frac{Q_{do}}{K_{u}}\left( {\kappa_{{rest}\; 1} + \kappa_{{rest}\; 2}} \right)}} \right)}} & \left( {9a} \right)\end{matrix}$

K_(b) _(Cit) is the approximated clearance value for citrate. Thisclearance is calculated for the actual flow rates using a mass transfervalue of K₀A_(Cit)=0,212*K₀A_(Urea) in the corresponding K_(u) formula.

FIG. 4 shows the conductivity values upstream and downstream thedialyzer after setting the fresh dialysis fluid sodium concentration forrunning an isotonic dialysis treatment.

It is worth to mention that the plasma conductivity might be alsomeasured using conductivity steps and applying the methods described inpublications n. EP 547025 and/or in EP 920877. This alternative oradditional estimation of plasma conductivity may further improve theplasma conductivity estimation made with the previously describedtechnique.

Factor k (namely, k_(rest1), k_(rest2), and k_(rest3)—see also thefollowing formulas (10) and (11)) defines the effect on the conductivitydue to other components in the dialysis fluid different from thecomponents already treated and included in the respective formula. Thus,the effect of salts containing calcium, magnesium, lactate, phosphate,and sulphate may have upon the conductivity. The effect created by thesecomponents is most often small, and does not vary considerably betweenthe dialysis treatments.

In order to obtain a dialysis fluid sodium implementing isonatremicdialysis, i.e. c_(di,Na,set,isoNa), a adjustment factorc_(di,Na,isoNa,adj) needs to be applied to make the sodium concentrationof dialysate out from the dialyzer matching the sodium concentration ofdialysis fluid at the inlet of the dialyzer:c _(di,Naset,isoNa) =c _(di,Na,κ) _(p,pre) +_(cdi,Na,isoNa,adj)   (10)

where:

$\begin{matrix}{c_{{di},{Na},{isoNa},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}{M_{\kappa_{KCl}}\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)}} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}} \right)}} & (11)\end{matrix}$

or where the adjustment factor also takes care of citrate according tothe following relationship:

$\begin{matrix}{c_{{di},{Na},{isoNa},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{{Na}_{3}{Cit}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\alpha^{- 3}} + {0.125\alpha^{- 2}} + {0.706\alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{{di},{{Na}_{3}{Cit}}}} \right)++}{M_{\kappa_{KCl}}\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)}} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}} \right)}} & \left( {11a} \right)\end{matrix}$

For K_(b) _(Cit) calculation see above.

In order to obtain a dialysis fluid sodium implementing isonatrikalemicdialysis, i.e. C_(di,Na,set,isoNa+K), an adjustment factorc_(di,Na,isoNa+K.adj) needs to be applied to make the sum of sodium andpotassium concentrations of dialysate out from the dialyzer matching thecorresponding sum of concentrations of dialysis fluid at the inlet ofthe dialyzer:c _(di,Na,set,isoNa+K) =c _(di,Na,κ) _(p,pre) +c _(di,Na,isoNa+K,adj)  (12)

where:

$\begin{matrix}{c_{{di},{Na},{{isoNa} + K},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right)\left( {{\alpha*c_{{pw},K}} - c_{{di},K}} \right)} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}} \right)}} & (13)\end{matrix}$

or where the adjustment factor also takes care of citrate according tothe following relationship:

$\begin{matrix}{c_{{di},{Na},{{isoNa} + K},{adj}} = {{- \frac{1}{M_{\kappa_{NaCl}}}}\left( {{\left( {M_{\kappa_{{NaHCO}_{3}}} - M_{\kappa_{NaCl}}} \right)\left( {{\frac{1}{\alpha}*c_{{pw},{HCO}_{3}}} - c_{{di},{HCO}_{3}}} \right)} + {\left( {M_{\kappa_{NaAc}} - M_{\kappa_{NaCl}}} \right){\left( {{\frac{1}{\alpha}*c_{{pw},{Ac}}} - c_{{di},{Ac}}} \right)++}\frac{K_{b_{Cit}}}{K_{u}}\left( {M_{{Na}_{3}{Cit}} - {3M_{\kappa_{NaCl}}}} \right){\left( {{\left( {{0.167\alpha^{- 3}} + {0.125\alpha^{- 2}} + {0.706\alpha^{- 1}}} \right)*c_{{pw},{{Na}_{3}{Cit}}}} - c_{{di},{{Na}_{3}{Cit}}}} \right)++}\left( {M_{\kappa_{KCl}} - M_{\kappa_{NaCl}}} \right)\left( {{\alpha*c_{{pw},K}} - c_{{di},k}} \right)} + {\frac{Q_{do}}{K_{u}}\kappa_{{rest}\; 3}}} \right)}} & \left( {13a} \right)\end{matrix}$

For K_(b) _(Cit) calculation see above.

Once the set point for sodium is calculated, the control unit drives theregulating means 10 for regulating the conductivity or the concentrationof the substance in the fresh dialysis fluid and sets the parametervalue for the dialysis fluid in the dialysis fluid supply line 8 at thecalculated set point.

With respect to all the above sodium concentrations set for theisotonic, isonatremic, and isonatrikalemic dialysis treatments, it isworth to note that the calculated and proposed concentration shall bewithin the isotonic sodium set user limits.

These limits may be chosen by the operator before isotonic dialysisstart, within the following limits:

-   -   For instance, the absolute safety range (e.g. 120±160 mmol/l);    -   the sodium range corresponding to the conductivity allowed range        of the machine (e.g. 12÷16 mS/cm), given the used bag and the        prescribed bicarbonate.

Generally, if the calculated sodium concentration value for the setfalls outside the user range, the isotonic dialysis should bede-activated and/or at least a warning is given to the operator.

Hence, the output of the described task is a new value for sodiumconcentration in the dialysis fluid, which is used as sodium set valuefor the regulating means (i.e. concentrate dosing system) when isotonicdialysis is active.

Advantageously, the changes to sodium set value will not affect thebicarbonate set value, which remains the one set by the operator.

In order to have a further degree of freedom for sodium set adjustment,before applying it to the remainder of the treatment, an additionaloffset may also be applied. This additional offset can be differentdepending on the isotonic dialysis type.

After the application of sodium adjustments above described, the inletconductivity correspondent to the fresh dialysis fluid sodiumconcentration determined with Eq. 8, 10, or 12 shall then be keptconstant throughout the remainder of the treatment.

After the setting of the sodium set point for the isotonic treatment,the plasma conductivity may be further calculated/monitored using commonprocedures, such as those described in patents EP 547025 or in EP 920877to monitor PC throughout the treatment.

During the identification phase (i.e. plasma conductivity initialestimate), the sodium setting is likely to be too high, leading tounintended sodium load. The time for this estimation may slightly vary,but as an average is about 15 minutes; accordingly, the magnitude of theerror is in the range of 5 mmol/l (of course varying with how well theexpected plasma conductivity matches the actual plasma conductivity, aswell as the magnitude of the isotonic adjustment).

To maintain the patient's sodium balance during the dialysis treatment,the calculated sodium set value must be adjusted to compensate for anyadditional unwanted sodium load to the patient.

Moreover, if common procedures such as those described in patents EP547025 or in EP 920877 to monitor plasma conductivity throughout thetreatment are used (e.g. Diascan measurements), a sodium transfer willresult from the conductivity steps (10 mmol/L for 120 s for example).This sodium transfer can be either in the positive or negativedirection.

Such unintended transfers may need to be compensated for in order tomaintain the desired sodium balance during the treatment.

In order to make the treatment truly isotonic (or better, to minimizethe tonicity gradient between the dialysis fluid and the blood), suchunintended transfers need to be compensated for as a whole.

In order to manage multiple deviations e.g. from Diascan measurements,the compensation may be implemented by integrating some, or possibly anydeviation from the intended sodium set point (i.e. the sodiumconcentration that is set after the measurement of the isoconductivity,c_(di,Na,set)) and then compensate for this over the remaining time oftreatment (T−t, where T is the total treatment time and t is the elapsedtreatment time).

The applied compensated sodium concentration set point may be calculatedaccording to the following formula:

$c_{{di},{Na},{set},{compensated}} = {c_{{di},{Na},{set}} + {\sum\limits_{i}{\frac{1}{T - t_{i}}{\overset{t_{i} + {\Delta\; t_{i}}}{\int\limits_{t_{i}}}{\left( {c_{{di},{Na},{set}} - c_{{di},{Na},{actual},i}} \right){dt}}}}}}$

where c_(di,Na,set), is the sodium setpoint calculated by the describedalgorithm (in other terms c_(di,Na,set) may be c_(di,Na,set,isotonic),c_(di,Na,set,isoNa), c_(di,Na,set,isoNa+K); cf. formulas the actual 8,10, and 12), c_(di,Na,actual) is the actual dialysis fluid sodiumconcentration set point used during the treatment at the time anadditional compensation is to be applied for (note that c_(di,Na,actual)may deviate from c_(di,Na,set), due to both the initial estimation ofisoconductivity and/or the plasma conductivity monitoring procedures,e.g. Diascan steps).

The compensation may be or may be not activated once c_(di,Na,set) hasbeen calculated (for example about 15 minutes after treatment start,i.e. at the end of the identification phase), and may (or may not) takethe past history into account so that any sodium transfer during theisoconductivity identification phase is also compensated.

The compensation may be applied after every sodium i-th deviation, i.e.,when sodium is equal to c_(di,Na,actual,i) for a duration of Δt_(i).Hence, also aborted Diascan measures may be taken into account (in thiscase, Δt may be lower than the forecast conductivity step).

Instead of applying a single compensation factor for each deviation, apotential alternative is to apply an integral controller, which, on thebasis of the current error on applied sodium set vs.isotonic/isonatremic/isonatrikalemic set found and on the time stillavailable, applies automatically a corrected set.

The invention claimed is:
 1. A method for setting parameters in anapparatus for extracorporeal blood treatment, the apparatus comprising:a filtration unit having a primary chamber and a secondary chamberseparated by a semi-permeable membrane; a blood withdrawal line in fluidcommunication with an inlet of the primary chamber; a blood return linein fluid communication with an outlet of the primary chamber, the bloodwithdrawal line and the blood return line configured for connection to apatient cardiovascular system; a dialysis supply line in fluidcommunication with an inlet of the secondary chamber; a dialysiseffluent line in fluid communication with an outlet of the secondarychamber; a preparation device for preparing dialysis fluid, thepreparation device in fluid communication with the dialysis supply lineand including a regulating device for regulating composition of thedialysis fluid; a sensor for measuring a parameter value of dialysate inthe dialysis effluent line, the parameter value of the dialysate beingat least one chosen from a group consisting of: (i) conductivity of thedialysate; (ii) a conductivity-related parameter of the dialysate; (iii)concentration of at least a substance in the dialysate; or (iv) aconcentration-related parameter of at least a substance in thedialysate; and a control unit communicating with the sensor to receivethe parameter value of the dialysate, the control unit furthercommunicating with the regulating device and calculating a valuerepresentative of plasma conductivity, the method comprising: setting aparameter value for dialysis fluid in the dialysis supply line at aninitial set point, the parameter value of the dialysis fluid being atleast one chosen from a group consisting of: (i) conductivity of thedialysis fluid; (ii) a conductivity-related parameter of the dialysisfluid; (iii) concentration of at least a substance in the dialysisfluid; or (iv) a concentration-related parameter of at least a substancein the dialysis fluid; after setting the parameter value of the dialysisfluid at the initial set point, circulating the dialysis fluid throughthe secondary chamber of the filtration unit so as to exchange withblood; circulating blood through the primary chamber of the filtrationunit; measuring at least an initial value of the dialysate downstream ofthe secondary chamber at the beginning of the treatment; andcalculating, based on the measured initial value of the dialysate, andon a corresponding parameter value of the dialysis fluid in the dialysissupply line, an initial plasma conductivity, wherein the circulating ofthe dialysis fluid through the secondary chamber up to the measuring ofthe initial value of the dialysate used for calculating the initialplasma conductivity is performed while maintaining the parameter valueof the dialysis fluid to be substantially constant.
 2. The methodaccording to claim 1, wherein the regulating device modifies a dialysisfluid composition by changing the conductivity of the dialysis fluid orby changing the concentration of at least one substance in the dialysisfluid, and wherein the preparation device prepares a dialysis fluidcontaining at least a substance, the substance including sodium, and theregulating device regulating the concentration of at least the substancein the dialysis fluid.
 3. The method according to claim 2, wherein theparameter value for the dialysis fluid is set at the initial set pointso that a dialysis fluid conductivity matches a first estimate of plasmaconductivity of the blood, the method further comprising: calculating aninitial set point of a substance concentration in the dialysis fluid,wherein a regulation of dialysis fluid conductivity in the supply lineby the regulating device is derived from the calculated initial setpoint of the substance.
 4. The method according to claim 3, wherein theinitial set point of the substance in the dialysis fluid is calculatedas a function of: (i) the concentration of at least a further substancein the dialysis fluid, the substance, whose concentration is to be set,being different from the further substance, wherein the furthersubstance is selected from the group consisting of bicarbonate,potassium, calcium, magnesium, acetate, lactate, citrate, phosphate, andsulphate, or (ii) the concentration of at least two substances selectedfrom the group consisting of bicarbonate, potassium, acetate, andcitrate.
 5. The method according to claim 3, wherein the initial setpoint of the substance in the dialysis fluid is calculated as a functionof an estimated plasma concentration of one or more substances selectedfrom the group consisting of sodium, potassium, calcium, magnesium,bicarbonate, acetate, lactate, citrate, phosphate, and sulphate.
 6. Themethod according to claim 3, wherein the initial set point of thesubstance in the dialysis fluid is calculated as a function of at leastone of the group consisting of: (i) a weighted difference inconcentration of at least one further substance in the dialysis fluidand in the plasma, the substance, whose concentration is to be set,being different from the at least one further substance, the at leastone further substance chosen from a group consisting of bicarbonate,potassium, calcium, magnesium, acetate, lactate, citrate, phosphate, andsulphate, (ii) a molar conductivity of at least one substance in thedialysis fluid chosen from a group consisting of acids and salts ofbicarbonate (HCO₃ ⁻), chloride (Cl⁻), acetate (CH₃COO⁻), lactate (C₃H₅O₃⁻), citrate (C₆H₅O₇ ³⁻), phosphate (PO₄ ³⁻) and sulphate (SO₄ ²⁻),wherein the salts are formed with sodium, potassium, calcium, ormagnesium, (iii) at least a flow rate of dialysate at the outlet of thesecondary chamber, or (iv) at least an efficiency parameter of thefiltration unit.
 7. The method according to claim 1, further comprising,after calculating the initial plasma conductivity, causing theregulating device to change a content of a substance in the dialysisfluid to reach a set point for the substance, the set point being afunction of the calculated initial plasma conductivity.
 8. The methodaccording to claim 1, further comprising measuring at least the initialparameter value of the dialysate in the dialysis effluent linedownstream of the secondary chamber as soon as the exchange process inthe filtration unit reaches stable conditions, the method determiningthat stable conditions for the exchange process have been reached whenone or more of the following conditions occurs: a first derivative of amedian or average value of the conductivity of the dialysate is lowerthan a first threshold for a specified time window, a first derivativeof a value of conductivity of the dialysate is lower than a firstthreshold for a specified time window, a first derivative of a filteredvalue of conductivity of the dialysate is lower than a first thresholdfor a specified time window, the filtered value being a value filteredeither by a median filter, a linear filter, a finite impulse responsefilter, or an infinite impulse response filter, a second derivative ofthe median or average value of the conductivity of the dialysate islower than a second threshold for a specified time window, a secondderivative of the value of conductivity of the dialysate is lower than afirst threshold for a specified time window, a second derivative of thefiltered value of conductivity of the dialysate is lower than a firstthreshold for a specified time window, a change or a relative change ofthe value of conductivity of the dialysate or a filtered version of thevalue of the conductivity with respect to a fixed previous point in timeis below a first threshold; a change or a relative change of the valueof conductivity of the dialysate or a filtered version of the value ofthe conductivity with respect to a fixed time interval backwards isbelow a first threshold, a prefixed time has lapsed after startingcirculation of both blood and dialysis fluid in the filtration unit, thepre-fixed time being not more than fifteen minutes, or a variable timehas lapsed after starting circulation of both blood and dialysis fluidin the filtration unit, the variable time being a function of at least aparameter of the apparatus, wherein during the step of determining thereaching of stable conditions, the method includes preventing changes ina dialysis fluid flow rate.
 9. The method according to claim 8, furthercomprising determining, once the exchange process in the filtration unitreaches stable conditions, at least an initial conductivity of thedialysis fluid upstream of the secondary chamber, the determinationexecuted either by receiving a dialysis fluid conductivity set value orby receiving a signal from a sensor for measuring a conductivity-relatedvalue of the dialysis fluid in the dialysis fluid supply line.
 10. Themethod according to claim 1, wherein the plasma conductivity iscalculated as a function of at least one in the group consisting of: (i)a dialysate flow rate at the outlet of the secondary chamber, (ii) ablood flow rate in the blood lines, (iii) at least an efficiencyparameter of the filtration unit, and (iv) an initial conductivity ofthe dialysate and a conductivity of the dialysis fluid in the dialysissupply line.
 11. The method according to claim 1, wherein the plasmaconductivity is calculated according to one of the formulas in the groupconsisting of:${\kappa_{p,1}^{\prime} = {\kappa_{0,{do}} + {\frac{Q_{do}}{Q_{bset}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}},$wherein κ_(p,1) is a plasma conductivity first estimate, Q_(do) is adialysate flow rate at the outlet of the secondary chamber, Q_(bset) isa set blood flow rate at the inlet of the primary chamber, κ_(0,di) is adialysis fluid conductivity at the inlet of the secondary chamber for apure electrolyte solution, and κ_(0,do) is a dialysate conductivity atthe outlet of the secondary chamber for a pure electrolyte solution, and${\kappa_{p,1}^{''} = {\kappa_{0,{di}} + {\frac{Q_{do}}{K_{u}}\left( {\kappa_{0,{do}} - \kappa_{0,{di}}} \right)}}},$wherein κ_(p,1) is a plasma conductivity first estimate, Q_(do) is adialysate fluid flow rate at the outlet of the secondary chamber, K_(u)is a filtration unit clearance for urea, κ_(0,di) is a dialysis fluidconductivity at the inlet of the secondary chamber for a pureelectrolyte solution, and κ_(0,do) is a dialysate conductivity at theoutlet of the secondary chamber for a pure electrolyte solution.
 12. Themethod according to claim 1, further comprising, after setting thedialysis fluid conductivity to be substantially equal to the calculatedinitial plasma conductivity, calculating a second estimate of theinitial plasma conductivity, the second estimate calculation based on asecond determined initial conductivity of the dialysate and on a secondcorresponding conductivity of the dialysis fluid in the dialysis supplyline, wherein the second estimate is calculated while maintaining thedialysis fluid conductivity substantially constant and substantiallyequal to the calculated initial plasma conductivity, the method furthercomprising directing, after calculating the second estimate of theinitial plasma conductivity, the regulating device to cause a change inthe composition of the dialysis fluid and to set the dialysis fluidconductivity substantially equal to the second estimate.
 13. A methodfor setting the parameters in an apparatus for extracorporeal bloodtreatment, the apparatus comprising: a filtration unit having a primarychamber and a secondary chamber separated by a semi-permeable membrane;a blood withdrawal line in fluid communication with an inlet of theprimary chamber; a blood return line in fluid communication with anoutlet of the primary chamber, the blood withdrawal line and the bloodreturn line configured for connection to a patient cardiovascularsystem; a dialysis supply line in fluid communication with at least oneof an inlet of the secondary chamber, the blood withdrawal line, or theblood return line; a dialysis effluent line in fluid communication withan outlet of the secondary chamber; a preparation device for preparingdialysis fluid, the preparation device in fluid communication with thedialysis supply line and comprising a regulating device for regulatingcomposition of the dialysis fluid; and a control unit communicating withthe regulating device and receiving a value representative of a firstparameter, the first parameter selected from the group consisting of:(i) a plasma conductivity, (ii) a plasma conductivity-related parameter,(iii) a concentration of at least a substance sodium in blood, and (iv)a concentration-related parameter of at least a substance sodium inblood, the method comprising: setting a second parameter for thedialysis fluid in the dialysis supply line at a set point, the secondparameter being at least one selected from the group consisting of: (i)a conductivity of the dialysis fluid, (ii) a conductivity-relatedparameter of the dialysis fluid, (iii) a concentration of at least asubstance in the dialysis fluid, and (iv) a concentration-relatedparameter of at least a substance in the dialysis fluid, wherein settingthe second parameter includes calculating the second parameter as afunction of a main contribution term based on the first parameter and asa function of an adjustment contribution term based on a concentrationof at least a substance in the dialysis fluid, the substance in thedialysis fluid selected from the group consisting of: bicarbonate,potassium, acetate, lactate, citrate, magnesium, calcium, sulphate andphosphate, and wherein the adjustment contribution term is an adjustmentcontribution applied to the sodium concentration set point forisoconductive dialysis, and wherein the adjustment contribution appliedto the sodium concentration set point for the isoconductive dialysisprovides a treatment selected from the group consisting of: isotonicdialysis, isonatremic dialysis, isonatrikalemic dialysis and a treatmentthat removes from, or adds to, the plasma a defined amount of at least asubstance.
 14. The method according to claim 13, wherein the adjustmentcontribution term is calculated as a function of at least one selectedfrom the group consisting of: (i) a concentration of two or moresubstances in the dialysis fluid selected from the group consisting of:bicarbonate, potassium, acetate, lactate, citrate, magnesium, calcium,sulphate, and phosphate, (ii) a difference in concentration of one ormore substances in the dialysis fluid, and the corresponding samesubstances in the blood, the substances being chosen from the groupconsisting of: bicarbonate, potassium, acetate, lactate, and citrate,(iii) molar conductivities of one or more substances in the dialysisfluid chosen from the group consisting of: sodium bicarbonate (NaHCO₃),sodium chloride (NaCl), sodium acetate (NaCH₃COO), potassium chloride(KCl), sodium lactate (NaC₃H₅O₃), and trisodium citrate (Na₃C₆H₅O₇),(iv) a difference between a first molar conductivity of a substancechosen from the group consisting of: sodium bicarbonate (NaHCO₃), sodiumacetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), sodium lactate(NaC₃H₅O₃), potassium chloride (KCl), and a molar conductivity of sodiumchloride (NaCl), (v) an estimated or measured plasma water concentrationof one or more substances chosen from the group consisting of:bicarbonate, potassium, acetate, lactate, and citrate, and (vi) at leasta ratio between a dialysate flow rate at the outlet of the secondarychamber and an efficiency parameter of the filtration unit.
 15. Themethod according to claim 13, wherein the first parameter is theconcentration of sodium in the blood, and wherein the second parameteris the conductivity of the dialysis fluid or the concentration of sodiumin the dialysis fluid.
 16. The method according to claim 13, wherein themain contribution term is a dialysis fluid concentration of sodium at anisoconductive dialysis.
 17. The method according to claim 13, furthercomprising: driving the regulating device for regulating theconductivity or the concentration of at least a substance in thedialysis fluid, and setting the second parameter for the dialysis fluidin the dialysis supply line at the calculated set point.
 18. The methodaccording to claim 13, further comprising calculating the adjustmentcontribution term as an algebraic sum of at least two components, afirst component being a function of a difference in concentration of atleast a first substance in the dialysis fluid, and the same substance inthe blood plasma, and a second component being a function of a weighteddifference in concentration of at least a second substance in thedialysis fluid, and the same second substance in the blood plasma,wherein the first and second substances are chosen from the groupconsisting of: bicarbonate anions (HCO₃ ⁻), acetate anions (CH₃COO⁻),citrate anions (C₆H₅O₇ ³⁻), and potassium ions (K⁺).
 19. The methodaccording to claim 13, further comprising calculating the adjustmentcontribution term as an algebraic sum of at least two components, afirst component being a function of a concentration of at least a firstsubstance in the dialysis fluid or blood plasma, and a second componentbeing a function of a concentration of at least a second substance inthe dialysis fluid or blood plasma, wherein the first and secondsubstances are chosen from the group consisting of: bicarbonate anions(HCO₃ ⁻), acetate anions (CH₃COO⁻), citrate anions (C₆H₅O₇ ³⁻), andpotassium ions (K⁺).
 20. The method according to claim 13, furthercomprising calculating the plasma conductivity as a function of at leastone selected from the group consisting of: (i) a dialysate flow rate atthe outlet of the secondary chamber and a blood flow rate in the bloodlines, (ii) at least an efficiency parameter of the filtration unit, and(iii) at least an initial conductivity of dialysate in the dialysiseffluent line and of at least a conductivity of the dialysis fluid inthe dialysis supply line.
 21. The method according to claim 13, furthercomprising: allowing selection of at least one treatment mode selectedfrom the group consisting of: isotonic dialysis, isonatremic dialysisand isonatrikalemic dialysis, and driving the regulating device as afunction of plasma conductivity and of the selected treatment mode toset either a desired dialysis fluid inlet conductivity or a desireddialysis fluid inlet sodium concentration.